Piperidines promote release of growth hormone

ABSTRACT

The present invention is directed to certain piperidines, pyrrolidines, and hexahydro-1H-azepines of the general structural formula: ##STR1## wherein B is selected from: ##STR2## and R 1 , R 1a , R 2a , R 3a , R 3b , R 4 , R 4a , R 4b , R 5 , D,E, X, Y, n, x and y are as defined herein. These compounds promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to treat physiological or medical conditions characterized by a deficiency in growth hormone secretion, such as short stature in growth hormone deficient children, and to treat medical conditions which are improved by the anabolic effects of growth hormone. Growth hormone releasing compositions containing such compounds as the active ingredient thereof are also disclosed.

This application is based on provisional application No. 60/026,054filed Sep. 13, 1996.

BACKGROUND OF THE INVENTION

Growth hormone, which is secreted from the pituitary, stimulates growthof all tissues of the body that are capable of growing. In addition,growth hormone is known to have the following basic effects on themetabolic processes of the body: (1) Increased rate of protein synthesisin all cells of the body; (2) Decreased rate of carbohydrate utilizationin cells of the body; (3) Increased mobilization of free fatty acids anduse of fatty acids for energy. A deficiency in growth hormone secretioncan result in various medical disorders, such as dwarfism.

Various ways are known to release growth hormone. For example, chemicalssuch as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon,vasopressin, and insulin induced hypoglycemia, as well as activitiessuch as sleep and exercise, indirectly cause growth hormone to bereleased from the pituitary by acting in some fashion on thehypothalamus perhaps either to decrease somatostatin secretion or toincrease the secretion of the known secretagogue growth hormonereleasing factor (GRF) or an unknown endogenous growth hormone-releasinghormone or all of these.

In cases where increased levels of growth hormone were desired, theproblem was generally solved by providing exogenous growth hormone or byadministering GRF or a peptidal compound which stimulated growth hormoneproduction and/or release. In either case the peptidyl nature of thecompound necessitated that it be administered by injection. Initiallythe source of growth hormone was the extraction of the pituitary glandsof cadavers. This resulted in a very expensive product and carried withit the risk that a disease associated with the source of the pituitarygland could be transmitted to the recipient of the growth hormone.Recombinant growth hormone has become available which, while no longercarrying any risk of disease transmission, is still a very expensiveproduct which must be given by injection or by a nasal spray. Othercompounds have been developed which stimulate the release of endogenousgrowth hormone such as analogous peptidyl compounds related to GRF orthe peptides of U.S. Pat. No. 4,411,890. These peptides, whileconsiderably smaller than growth hormones are still susceptible tovarious proteases. As with most peptides, their potential for oralbioavailability is low. Non peptidal growth hormone secretagogues aredisclosed in e.g., U.S. Pat. Nos. 5,206,235, 5,283,241, 5,284,841,5,310,737, 5,317,017, 5,374,721, 5,430,144, 5,434,261, 5,438,136,5,492,916, 5,494,919, 5,494,920, and 5,536,716. Other growth hormonesecretagogues are disclosed e.g., in PCT Patent Publications WO94/13696, WO 94/19367, WO 95/03289, WO 95/03290, WO 95/09633, WO95/11029, WO 95/12598, WO 95/13069, WO 95/14666, WO 95/16675, WO95/16692, WO 95/17422, WO 95/17423, WO 95/34311, WO 96/02530 and WO96/22997. The instant compounds are low molecular weight peptide analogsfor promoting the release of growth hormone which have good stability ina variety of physiological environments and which may be administeredparenterally, nasally or by the oral route.

SUMMARY OF THE INVENTION

The instant invention is directed to certain piperidines, pyrrolidines,and hexahydro-1H-azepines which have the ability to stimulate therelease of natural or endogenous growth hormone. The compounds thus havethe ability to be used to treat conditions which require the stimulationof growth hormone production or secretion such as in humans with adeficiency of natural growth hormone or in animals used for food or woolproduction where the stimulation of growth hormone will result in alarger, more productive animal. Thus, it is an object of the instantinvention to describe the piperidine compounds. It is a further objectof this invention to describe procedures for the preparation of suchcompounds. A still further object is to describe the use of suchcompounds to increase the secretion of growth hormone in humans andanimals. A still further object of this invention is to describecompositions containing the piperidine compounds for the use of treatinghumans and animals so as to increase the level of growth hormonesecretions. Further objects will become apparent from a reading of thefollowing description.

DESCRIPTION OF THE INVENTION

The novel piperidines, pyrrolidines, and hexahydro-1H-azepines of theinstant invention are described by structural Formula I: ##STR3##wherein: R¹ is selected from the group consisting of:

C₁ -C₁₀ alkyl, -aryl-, aryl (C₁ -C₆ alkyl)-,

heteroaryl-, heteroaryl(C₁ -C₆ alkyl)-,

(C₃ -C₇ cycloalkyl)-(C₁ -C₆ alkyl)-,

(C₁ -C₅ alkyl)-K-(C₁ -C₅ alkyl)-,

aryl-(C_(O-C) ₅ alkyl)-K-(C₁ -C₅ alkyl)-,

heteroaryl-(C₀ -C₅ alkyl)-K-(C₁ -C₅ alkyl)-, and

(C₃ -C₇ cycloalkyl)-(C₀ -C₅ alkyl)-K-(C₁ -C₅ alkyl)-,

wherein K is --O--, --S(O)_(m) --, --N(R²)C(O)--,--C(O)N(R²)--,--OC(O)--, --C(O)O--, --CR² ═CR² -- or --C.tbd.C--,

wherein R² and the alkyl groups may be further substituted with 1 to 9halo, --S(O)_(m) R^(2a), 1 to 3 of --OR^(2a), or --C(O)OR^(2a), andwherein aryl is phenyl or naphthyl, and heteroaryl is selected fromindolyl, thiophenyl, benzofuranyl, benzothiopheneyl, aza-indolyl,pyridinyl, quinolinyl, and benzimidazolyl, wherein aryl and heteroarylare unsubstituted or substituted with phenyl, phenoxy, halophenyl, 1 to3 of --C₁ -C₆ alkyl, 1 to 3 of halo, 1 to 2 of --OR², methylenedioxy,--S(O)_(m) R², 1 to 2 of --CF₃, --OCF₃, nitro, --N(R²)(R²),--N(R²)C(O)(R²), --C(O)OR², --C(O)N(R²)(R²), --SO₂ N(R²)(R²), --N(R²)SO₂-aryl, or --N(R²)SO₂ R² ;

R^(1a) is hydrogen or C₁ -C₄ alkyl;

R² is selected from the group consisting of:

hydrogen, --C₁ -C₆ alkyl, --C₃ -C₇ cycloalkyl, and --CH₂ -phenyl,

wherein the alkyl or the cyloalkyl is unsubstituted or substituted withhydroxyl, C₁ -C₃ alkoxy, thioalkyl, C(O)OR^(2a), and where, if two --C₁-C₆ alkyl groups are present on one atom, they may be joined to form aC₃ -C₈ cyclic ring being selected from the group consisting ofpyrrolidine, piperidine, piperazine, morpholine, thiomorpholine,optionally substituted by hydroxyl;

R^(2a) is hydrogen or C₁ -C₆ alkyl;

B is selected from: ##STR4## R³ is selected from: hydrogen, --(CH₂)_(r)phenyl, --(CH₂)_(r) pyridyl, --(CH₂)_(r) thienyl, --(CH₂)_(r)benzimidazolyl, --(CH₂)_(r) quinolinyl, --(CH₂)_(r) naphthyl,--(CH₂)_(r) indolyl, --C₁ -C₁₀ alkyl, _(C) ₃ -C₇ cycloalkyl,

where the phenyl, pyridyl, naphthyl, indolyl, thienyl, benzimidazolyl,quinolinyl, and C₃ -C₇ cycloalkyl rings may be substituted by 1 to 3substituents selected from the group consisting of: C₁ -C₆ alkyl,halogen, --OR², --NHSO₂ CF₃, --(CH₂)_(r) OR⁶, --(CH₂)_(r) N(R²)(R⁶),--(CH₂)_(r) (R⁶), --(CH₂)_(r) C(O)OR², --(CH₂)_(r) C(O)OR⁶, --(CH₂)_(r)OC(O)R², --(CH₂)_(r) OC(O)R⁶, --(CH₂)_(r) C(O)R², --(CH₂)_(r) C(O)R⁶,--(CH₂)_(r) C(O)N(R²)(R²), --(CH₂)_(r) C(O)N(R²)(R⁶), --(CH₂)_(r)N(R²)C(O)(R²), --(CH₂)_(r) N(R²)C(O)R⁶ --(CH²)_(r) N(R⁶)C(O)R²,--(CH₂)_(r) N(R⁶)C(O)R⁶, --(CH₂)_(r) N(R²)C(O)OR², --(CH₂)_(r)N(R²)C(O)OR⁶, --(CH₂)_(r) N(R⁶)C(O)OR², --(CH₂)_(r) N(R⁶)C(O)OR⁶,--(CH₂)_(r) N(R²)C(O)N(R²)(R⁶), --(CH₂)_(r) N(R²)C(O)N(R²)(R²),--(CH₂)_(r) N(R⁶)C(O)N(R²)(R⁶), --(CH₂)_(r) N(R²)SO₂ R², --(CH₂)_(r)N(R⁶)SO₂ R², --(CH₂)_(r) N(R⁶)SO₂ R⁶, --(CH₂)_(r) OC(O)N(R²)(R⁶),--(CH₂)_(r) OC(O)N(R²)(R²), --(CH₂)_(r) SO₂ N(R²)(R⁶), --(CH₂)_(r)OC(O)N(R²)(R²), --(CH₂)_(r) SO₂ N(R²)(R⁶), --(CH₂)_(r) SO₂ N(R²)(R²),--(CH₂)_(r) N(R²)SO₂ N(R²)(R⁶), --(CH₂)_(r) N(R⁶)SO₂ N(R²)(R⁶),--(CH₂)_(r) S(O)_(m) R⁶, and --(CH₂)_(r) S(O)_(m) R² ;

R^(3a) and R^(3b) are independently selected from: hydrogen, phenyl,phenoxy, halophenyl, --C₁ -C₆ alkyl, halogen, --OR², methylenedioxy,--S(O)_(m) R², --CF₃, --OCF₃, nitro, --N(R²)(R²), --N(R²)C(O)(R²),--C(O)OR², --C(O)N(R²)(R²), --SO₂ N(R²)(R²), --N(R²)SO₂ -aryl, and--N(R²)SO² R² ;

E is selected from: --O--, --S--, --CH═CH--, ##STR5## which isoptionally substituted with a substituent selected from: halo, hydroxy,--N(R²)(R²), C₁ -C₆ alkyl and C₁ -C₆ alkoxy;

R⁴ and R⁵ are independently selected from hydrogen, C₁ -C₆ alkyl, andsubstituted C₁ -C₆ alkyl where the substituents are selected from halo,

hydroxy, phenyl, and C₁ -C₆ alkoxycarbonyl;

or R⁵ and R⁴ may be taken together to form --(CH₂)_(d) --L_(a) (CH₂)_(e)-- where L_(a) is --C(R²)₂ --, --O --, --S(O)_(m) -- or --N(R²)--, d ande are independently 1 to 3 and R² is as defined above;

R^(4a) and R^(4b) are independently selected from: hydrogen, C₁ -C₆alkyl, trifluoromethyl, phenyl, or substituted C₁ -C₆ alkyl where thesubstituents are selected from: imidazolyl, naphthyl, phenyl, indolyl,p-hydroxyphenyl, --OR², --S(O)_(m) R², --C(O)OR², C₃ -C₇ cycloalkyl,--N(R²)(R²), --C(O)N(R²)(R²); or R^(4a) and R^(4b) may independently bejoined to one or both of R⁴ or E (where E is other than --O--, --S--, or--CH═CH--) to form an alkylene bridge between the terminal nitrogen andthe alkyl portion of the R^(4a) or R^(4b) and the R⁴ E group, whereinthe bridge contain 1 to 8 carbons atoms; or R^(4a) and R^(4b) may bejoined to one another to form C₃ -C₇ cycloalkyl;

R⁶ is selected from: hydrogen, C₁ -C₆ alkyl, and (CH₂)_(v) aryl, whereinthe (CH₂)_(v) and alkyl groups may be optionally substituted by --O(R²),--S(O)_(m) R², --C(O)OR², --C(O)N(R²)(R²), --SO₂ N(R²)(R²), or--N(R²)C(O)N(R²)(R²), wherein the aryl group is selected from: phenyl,pyridyl, 1H-tetrazolyl, triazolyl, oxadiazolyl, pyrazolyl, thiadiazoyl,and benzimidazol-2-yl, which is optionally substituted with C₁ -C₆alkyl, C₃ -C₆ cycloalkyl, amino, or hydroxyl;

X is selected from the group consisting of: hydrogen, --C.tbd.N,--(CH₂)_(q) N(R²)C(O)R², --(CH₂)_(q) N(R²)C(O)(CH₂)_(t) aryl,--(CH₂)_(q) N(R²)SO₂ (CH₂)_(t) aryl, --(CH₂)_(q) N(R²)SO₂ R²,--(CH₂)_(q) N(R²)C(O)N(R²)(CH₂)_(t) aryl, --(CH₂)_(q)N(R²)C(O)N(R²)(R²), --(CH₂)_(q) C(O)N(R²)(R²), --(CH₂)_(q)C(O)N(R²)(CH₂)_(t) aryl, --(CH₂)_(q) C(O)OR², --(CH₂)_(q) C(O)O(CH₂)_(t)aryl, --(CH₂)_(q) OR², --CH₂)_(q) OC(O)R², --(CH₂)_(q) OC(O)(CH²)_(t)aryl, --(CH₂)_(q) OC(O)N(R²)(R²), --(CH₂)_(q) C(O)R², --(CH₂)_(q)C(O)(CH₂)_(t) aryl, --(CH₂)_(q) N(R²)C(O)OR², --(CH₂)_(q) N(R²)SO₂N(R²)(R²), --(CH₂)_(q) S(O)mR², and --(CH₂)_(q) S(O)m(CH₂)_(t) aryl,where R², (CH₂)_(q) and (CH₂)_(t) group may be optionally substitutedwith C₁ -C₄ alkyl, hydroxyl, C₁ -C₄ lower alkoxy, carboxyl, N(R²)(R²),CONH₂, S(O)_(m) CH₃, carboxylate C₁ -C₄ alkyl esters, or1H-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or1H-tetrazol-5-yl groups which may be optionally substituted withhalogen, --OR², --CON(R²)(R²), --C(O)OR², C₁ -C₄ alkyl, --S(O)_(m) R²,or 1H-tetrazol-5-yl;

Y is selected from the group consisting of:

hydrogen, C₁ -C₁₀ alkyl, --(CH₂)_(t) aryl, --(CH₂)_(q) (C₃ -C₇cycloalkyl), --(CH₂)_(q) --K--(C₁ -C₆ alkyl), --(CH₂)_(q) --K--(CH₂)_(t)aryl, --(CH₂)_(q) --K--(CH₂)_(t) (C₃ -C₇ cycloalkyl containing O, NR² S)and --(CH₂)_(q) --K--(CH₂)_(t) (C₃ -C₇ cycloalkyl), where K is --O--,--S(O)_(m) --, --C(O)NR² --, --CH═CH--, --C.tbd.C--, --N(R²)C(O)--,--C(O)NR² --, --C(O)O--, or --OC(O)--, and where the alkyl, R²,(CH₂)_(q) and (CH₂)_(t) groups are optionally substituted by C₁ -C₄alkyl, hydroxyl, C₁ -C₄ lower alkoxy, carboxyl, --CONH₂ or a carboxylateC₁ -C₄ alkyl ester, and aryl is phenyl, naphthyl, pyridyl,1-H-tetrazol-5-yl, thiazolyl, imidazoly, indolyl, oxadiazoyl,pyrimidinyl, thiadiazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl,quinolinyl, pyrrazinyl, or isothiazolyl which is optionally substitutedwith halogen, --OR², --C(O)OR², N(R²)(R²), --C(O)N(R²)(R²), nitro,cyano, benzyl, C₁ -C₄ alkyl, --S(O)_(m) R², or 1H-tetrazol-5-yl;

D is selected from: --N(R⁷)--, --S(O)_(m) --, --C(O)-- and --C(H)(R⁷)--,

wherein R⁷ is selected from: --R², --OR², --(CH₂)_(q) aryl, --C(O)R²,--C(O)(CH₂)_(q) aryl, --SO₂ R², --SO₂ (CH₂)_(q) aryl, --C(O)N(R²)(R²),--C(O)N(R²)(CH₂)_(q) aryl, --C(O)OR², 1-H-tetrazol-5-yl, --SO₂N(R²)aryl, --SO₂ N(R²)(R²) and the (CH₂)_(q) may be optionallysubstituted by C₁ -C₄ alkyl, and the R² and aryl may be optionallyfurther substituted with a substituent selected from: --OR^(2a),--O(CH₂)_(q) aryl, --C(O)OR^(2a), --C(O)(CH₂)_(q) aryl,--C(O)N(R^(2a))(R^(2a)), --C(O)N(R^(2a))(CH₂)_(l) aryl, halogen,--N(R^(2a))(R^(2a)), --C₁ -C₄ alkyl, 1,2,4-triazolyl, 1-H-tetrazol-5-yl,--C(O)NHSO₂ R^(2a), --S(O)_(m) R^(2a), --C(O)NHSO₂ (CH₂)_(q) aryl,--N(R²)C(O)N(R^(2a))(R^(2a)), --N(R^(2a))C(O)N(R^(2a))(CH₂)_(q) aryl,--N(R^(2a))(R^(2a)), --N(R^(2a))C(O)R^(2a)), --N(R^(2a))C(O)(CH₂)_(q)aryl, --OC(O)N(R^(2a))(R^(2a)), --OC(O)N(R^(2a))(CH₂)_(q) aryl;

l is 0, 1 or 2;

m is 0, 1, or 2;

n is 0, 1, or 2;

q is 0, 1, 2, 3, or 4;

r is 0, 1, 2, or 3;

t is 0, 1, 2, or 3;

v is 0, 1, or 2;

x is 0, 1, 2, or 3;

y is 0, 1, 2, or 3, with the proviso that if E is --O-- or --S--, y isother than 0 or 1, and with the further proviso that if E is --CH═CH--,y is other than 0;

and pharmaceutically acceptable salts and individual diastereomersthereof.

In the above structural formula and throughout the instantspecification, the following terms have the indicated meanings:

When n is 1 a pyrrolidine ring is formed, when n is 2 a piperidine ringis formed, and when n is 3 the ring is designated ahexahydro-1-H-azepine.

The alkyl groups specified above are intended to include those alkylgroups of the designated length in either a straight or branchedconfiguration and if two carbon atoms or more they may include a doubleor a triple bond. Exemplary of such alkyl groups are methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl,hexyl, isohexyl, allyl, propargyl, and the like.

The alkoxy groups specified above are intended to include those alkoxygroups of the designated length in either a straight or branchedconfiguration and if two or more carbon atoms in length, they mayinclude a double or a triple bond. Exemplary of such alkoxy groups aremethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiarybutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy,and the like.

The term "halogen" is intended to include the halogen atom fluorine,chlorine, bromine and iodine.

The term "aryl" within the present invention, unless otherwisespecified, is intended to include aromatic rings, such as carbocyclicand heterocyclic aromatic rings selected the group consisting of:phenyl, naphthyl, pyridyl, 1-H-tetrazol-5-yl, thiazolyl, imidazolyl,indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl,thiopheneyl, quinolinyl, pyrrazinyl, or isothiazolyl, which may beoptionally substituted by 1 to 3 of C₁ -C₆ alkyl, 1 to 3 of halogen, 1to 2 of OR₂, methylenedioxy, --S(O)_(m) R₂, 1 to 2 of --CF₃, --OCF₃,nitro, --N(R₂)C(O)(R₂), --C(O)OR₂, --C(O)N(R₂)(R₂), -1H-tetrazol-5-yl,--SO₂ N(R₂)(R₂), --N(R₂)SO₂ phenyl, or --N(R₂)SO₂ R₂, wherein R₂ is asdefined herein.

Certain of the above defined terms may occur more than once in the aboveformula and upon such occurrence each term shall be definedindependently of the other.

Preferred compounds of the instant invention include those of FormulaIa: ##STR6## wherein: R¹ is selected from the group consisting of:

C₁ -C₁₀ alkyl, -aryl-, aryl (C₁ -C₆ alkyl)-, heteroaryl-, heteroaryl(C₁-C₆ alkyl)-,

(C₃ -C₇ cycloalkyl)-(C₁ -C₆ alkyl)-,

(C₁ -C₅ alkyl)-K-(C₁ -C₅ alkyl)-,

aryl-(C₀ -C₅ alkyl)-K-(C₁ -C₅ alkyl)-,

heteroaryl-(C₀ -C₅ alkyl)-K-(C₁ -C₅ alkyl)-, and

(C₃ -C₇ cycloalkyl)-(C₀ -C₅ alkyl)-K-(C₁ -C₅ alkyl)-,

wherein K is --O--, --S(O)_(m) --, --N(R²)C(O)--,--C(O)N(R²)--,--OC(O)--, --C(O)O--, --CR² ═CR² -- or --C.tbd.C--,

wherein R² and the alkyl groups may be further substituted with 1 to 9halo, --S(O)MR^(2a), 1 to 3 of --OR^(2a), or --C(O)OR^(2a), and whereinaryl is phenyl or naphthyl, and heteroaryl is selected from indolyl,thiophenyl, benzofuranyl, benzothiopheneyl, aza-indolyl, pyrindinyl,quinolinyl, and benzimidazolyl, wherein aryl and heteroaryl areunsubstituted or substituted with phenyl, phenoxy, halophenyl, 1 to 3 of--C₁ -C₆ alkyl, 1 to 3 of halo, 1 to 2 of --OR², methylenedioxy,--S(O)_(m) R², 1 to 2 of --CF₃, --OCF₃, nitro, --N(R²)(R²),--N(R²)C(O)(R²), --C(O)OR², --C(O)N(R²)(R²), --SO₂ N(R²)(R²), --N(R²)SO₂-aryl, or --N(R²)SO₂ R² ;

R² is selected from the group consisting of:

hydrogen, --C₁ -C₆ alkyl, --C₃ -C₇ cycloalkyl, and --CH₂ -phenyl,wherein the alkyl or the cyloalkyl is unsubstituted or substituted withhydroxyl, C₁ --C₃ alkoxy, thioalkyl, --C(O)OR^(2a), and wherein, if two--C₁ -C₆ alkyl groups are present on one atom, the groups may beoptionally joined to form a C₃ -C₈ cyclic ring being selected from thegroup consisting of pyrrolidine, piperidine, piperazine, morpholine,thiomorpholine;

B is selected from: ##STR7## R³ is selected from: hydrogen, phenyl,pyridyl, naphthyl, indolyl, benzimidazolyl, thienyl, quinolinyl, wherethe phenyl, pyridyl, naphthyl, benzimidazolyl, thienyl, quinolinyl, andindolyl may be substituted by 1 to 3 substituents selected from thegroup consisting of: C₁ -C₆ alkyl, halogen, --OR², --(CH₂)_(r) OR⁶,--(CH₂)_(r) N(R²)(R⁶), --(CH₂)_(r) (R⁶), --(CH₂)_(r) C(O)OR²,--(CH₂)_(r) C(O)OR⁶, --(CH₂)_(r) C(O)R², --(CH₂)_(r) C(O)R⁶, --(CH₂)_(r)C(O)N(R²)(R²), --(CH₂)_(r) C(O)N(R²)(R⁶), --(CH₂)_(r) N(R²)C(O)(R²),--(CH₂)_(r) N(R²)C(O)R⁶, --(CH₂)_(r) N(R⁶)C(O)R², --(CH₂)_(r)N(R⁶)C(O)R⁶, --(CH₂)_(r) N(R²)C(O)OR², --(CH₂)_(r) N(R²)C(O)OR⁶,--(CH₂)_(r) N(R⁶)C(O)OR², --(CH₂)_(r) N(R⁶)C(O)OR⁶, --(CH₂)_(r)N(R²)C(O)N(R²)(R⁶), --(CH₂)_(r) N(R²)C(O)N(R²)(R²), --(CH₂)_(r)N(R⁶)C(O)N(R²)(R⁶), --(CH₂)_(r) N(R²)SO₂ R², --(CH₂)_(r) N(R⁶)SO₂ R²,--(CH₂)_(r) N(R⁶)SO₂ R⁶, --(CH₂)_(r) OC(O)N(R²)(R⁶), --(CH₂)_(r) SO₂N(R²)(R⁶), --(CH₂)_(r) SO₂ N(R²)(R⁶), --(CH₂)_(r) SO₂ N(R²)(R²),--(CH₂)_(r) S(O)_(m) R⁶, and --(CH₂)_(r) S(O)_(m) R² ;

R^(3a) and R^(3b) are independently selected from: hydrogen, phenyl,phenoxy, halophenyl, --C₁ -C₆ alkyl, halogen, --OR², methylenedioxy,--S(O)_(m) R², --CF₃, --OCF₃, nitro, --N(R²)(R²), --N(R²)C(O)(R²),--C(O)OR², --C(O)N(R²)(R²), --SO₂ N(R²)(R²), --N(R²)SO₂ -aryl, and--N(R²)SO² R² ;

E is selected from: --O--, --S--, --CH═CH--, ##STR8## which isoptionally substituted with a substituent selected from: halo, hydroxy,--N(R²)(R²), C₁ -C₆ alkyl and C₁ -C₆ alkoxy;

R⁴ and R⁵ are independently selected from hydrogen, C₁ -C₆ alkyl, andsubstituted C₁ -C₆ alkyl where the substituents are selected from halo,hydroxy, phenyl, and C1-C6 alkoxycarbonyl;

or R⁵ and R⁴ may be taken together to form --(CH₂)_(d) --L_(a) (CH₂)_(e)-- where L_(a) is --C(R²)₂ --, --O--, --S(O)_(m) -- or --N(R²)--, d ande are independently 1 to 3 and R² is as defined above;

R^(4a) and R^(4b) are independently selected from: hydrogen, C₁ -C₆alkyl, trifluoromethyl, phenyl, or substituted C₁ -C₆ alkyl where thesubstituents are selected from: imidazolyl, naphthyl, phenyl, indolyl,p-hydroxyphenyl, --OR², --S(O)_(m) R², --C(O)OR², C₃ -C₇ cycloalkyl,--N(R²)(R²), --C(O)N(R²)(R²); or R^(4a) and R^(4b) may independently bejoined to one or both of R⁴ or E (were E is other than --O--, --S--, or--CH═CH--) to form an alkylene bridge between the terminal nitrogen andthe alkyl portion of the R^(4a) or R^(4b) and the R⁴ E group, whereinthe bridge contain 1 to 5 carbons atoms; or R^(4a) and R^(4b) may bejoined to one another to form C₃ -C₇ cycloalkyl;

R⁶ is selected from: hydrogen, C₁ -C₆ alkyl, and (CH₂)_(v) aryl, whereinthe (CH₂)_(v) and alkyl groups may be optionally substituted by --O(R²),--S(O)_(m) R², --C(O)OR², --C(O)N(R²)(R²), --SO₂ N(R²)(R²), or--N(R²)C(O)N(R²)(R²), wherein the aryl group is selected from: phenyl,pyridyl, 1H-tetrazolyl, triazolyl, oxadiazolyl, pyrazolyl, thiadiazoyl,and benzimidazol-2-yl, which is optionally substituted with C₁ -C₆alkyl, C₃ -C₆ cycloalkyl, amino, or hydroxyl;

X is selected from the group consisting of: hydrogen, --C.tbd.N,--(CH₂)_(q) N(R²)C(O)R², --(CH₂)_(q) N(R²)C(O)(CH₂)_(t) aryl,--(CH₂)_(q) N(R²)SO₂ (CH₂)_(t) aryl, --(CH₂)_(q) N(R²)SO₂ R²,--(CH₂)_(q) N(R²)C(O)N(R²)(CH₂)_(t) aryl, --(CH₂)_(q)N(R²)C(O)N(R²)(R²), --(CH₂)_(q) C(O)N(R²)(R²), --(CH₂)_(q)C(O)N(R²)(CH₂)_(t) aryl, --(CH₂)_(q) C(O)OR², --(CH₂)_(q) C(O)O(CH₂)_(t)aryl, --(CH₂)_(q) OR², --(CH₂)_(q) OC(O)R², --(CH₂)_(q) OC(O)(CH²)_(t)aryl, --(CH₂)_(q) OC(O)N(R²)(R²), --(CH₂)_(q) C(O)R², --(CH₂)_(q)C(O)(CH₂)_(t) aryl, --(CH₂)_(q) N(R²)C(O)OR², --(CH₂)_(q) N(R²)SO₂N(R²)(R²), --(CH₂)_(q) S(O)_(m) R², and --(CH₂)_(q) S(O)_(m) (CH₂)_(t)aryl, where R², (CH₂)_(q) and (CH₂)_(t) group may be optionallysubstituted with C₁ -C₄ alkyl, hydroxyl, C₁ -C₄ lower alkoxy, carboxyl,N(R²)(R²), CONH₂, S(O)_(m) CH₃, carboxylate C₁ -C₄ alkyl esters, or1H-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or1H-tetrazol-5-yl groups which may be optionally substituted withhalogen, --OR², --CON(R²)(R²), --C(O)OR², C₁ -C₄ alkyl, --S(O)_(m) R²,or 1H-tetrazol-5-yl;

Y is selected from the group consisting of:

hydrogen, C₁ -C₁₀ alkyl, --(CH₂)_(t) aryl, --(CH₂)_(q) (C₃ -C₇cycloalkyl), --(CH₂)_(q) --K--(C₁ -C₆ alkyl), --(CH₂)_(q) --K--(CH₂)_(t)aryl, --(CH₂)_(q) --K--(CH₂)_(t) (C₃ -C₇ cycloalkyl containing O, NR² S)and --(CH₂)_(q) --K--(CH₂)_(t) (C₃ -C₇ cycloalkyl), where K is O,S(O)_(m), C(O)NR², CH═CH, C.tbd.C, N(R²)C(O), C(O)NR², C(O)O, or OC(O),and where the alkyl, R², (CH₂)_(q) and (CH₂)_(t) groups are optionallysubstituted by C₁ -C₄ alkyl, hydroxyl, C₁ -C₄ lower alkoxy, carboxyl,--CONH₂ or a carboxylate C₁ -C₄ alkyl ester, and aryl is phenyl,naphthyl, pyridyl, 1-H-tetrazol-5-yl, thiazolyl, imidazoly, indolyl,oxadiazoyl, pyrimidinyl, thiadiazolyl,pyrazolyl, oxazolyl, isoxazolyl,thiopheneyl, quinolinyl, pyrrazinyl, or isothiazolyl which is optionallysubstituted with halogen, --OR², --C(O)OR², N(R²)(R²), --C(O)N(R²)(R²),nitro, cyano, benzyl, C₁ -C₄ alkyl, --S(O)_(m) R², or 1H-tetrazol-5-yl;

D is selected from: --N(R⁷)--, -S(O)_(m) --, --C(O)-- and --C(H)(R⁷)--,

wherein R⁷ is selected from: --R², --(CH₂)_(q) aryl, --C(O)R², --SO₂ R²,C(O)N(R²)(R²), --C(O)OR², 1-H-tetrazol-5-yl, --SO₂ N(R²)aryl, --SO₂N(R²)(R²) and the (CH₂)_(q) may be optionally substituted by C₁ -C₄alkyl, and the R² and aryl may be optionally further substituted with asubstituent selected from: --OR^(2a), --C(O)OR^(2a),--C(O)N(R^(2a))(R^(2a)), halogen, --C₁ -C₄ alkyl, and the aryl isselected from of triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl,imidazolyl, and 1H-tetrazolyl;

l is 0, 1 or 2;

m is 0, 1, or 2;

q is 0, 1, 2, 3, or 4;

r is 0, 1, 2, or 3;

t is 0, 1, 2, or 3;

v is 0, 1, or 2;

x is 0, 1, 2, or 3;

y is 0, 1, 2, or 3, with the proviso that if E is --O-- or --S--, y isother than 0 or 1, and with the further proviso that if E is --CH═CH--,y is other than 0;

and pharmaceutically acceptable salts and individual diastereomersthereof.

More preferred compounds of the instant invention include those ofFormula Ib: ##STR9## wherein: ¹ is selected from the group consistingof: ##STR10## or their regioisomers where not specified; R² is selectedfrom the group consisting of:

hydrogen, --C₁ -C₆ alkyl, --C₃ -C₇ cycloalkyl, and --CH₂ -phenyl,wherein the alkyl or the cyloalkyl is unsubstituted or substituted withhydroxyl, C₁ -C₃ alkoxy, thioalkyl, --C(O)OR^(2a), and wherein, if two--C₁ -C₆ alkyl groups are present on one atom, the groups may beoptionally joined to form a C₃ --C₈ cyclic ring being selected from thegroup consisting of pyrrolidine, piperidine, piperazine, morpholine,thiomorpholine;

R^(2a) is hydrogen, or C₁ -C₄ alkyl;

B is selected from: ##STR11## R³ is selected from: hydrogen or phenyl,wherein the phenyl is substituted in the ortho position by a substituentselected from the group consisting of: C₁ -C₆ alkyl, halogen, --OR²,--(CH₂)_(r) OR⁶, --(CH₂)_(r) N(R²)(R⁶), --(CH₂)_(r) (R⁶), --(CH₂)_(r)C(O)OR², --(CH₂)_(r) C(O)OR⁶, --(CH₂)_(r) C(O)R², --(CH₂)_(r) C(O)R⁶,--(CH₂)_(r) C(O)N(R²)(R²), --(CH₂)_(r) C(O)N(R²)(R⁶), --(CH₂)_(r) SO₂N(R²)(R⁶), --(CH₂)_(r) SO₂ N(R²)(R²), --(CH₂)_(r) S(O)_(m) R⁶, and--(CH₂)_(r) S (O)_(m) R² ; R^(3a) and R^(3b) are independently selectedfrom: hydrogen, --C₁ -C₆ alkyl and halogen;

E is selected from: --O--, --CH═CH--, ##STR12## which is optionallysubstituted with a substituent selected from: halo, hydroxy,--N(R²)(R²), C₁ -C₆ alkyl and C₁ -C₆ alkoxy;

R⁴ and R⁵ are independently selected from hydrogen, C₁ -C₆ alkyl, andsubstituted C₁ -C₆ alkyl where the substituents are selected from halo,hydroxy, phenyl, and C₁ -C₆ alkoxycarbonyl;

or R⁵ and R⁴ may be taken together to form --(CH₂)_(d) --L_(a) (CH₂)_(e)-- where L_(a) is --C(R²)₂ --, --O--, --S(O)_(m) -- or --N(R²)--, d ande are independently 1 to 3 and R² is as defined above;

R^(4a) and R^(4b) are independently selected from: hydrogen, C₁ -C₆alkyl, or substituted C₁ -C₆ alkyl where the substituents are selectedfrom: imidazolyl, naphthyl, phenyl, indolyl, and p-hydroxyphenyl;

R⁶ is selected from: hydrogen, C₁ -C₆ alkyl, and (CH₂)_(v) aryl, whereinthe (CH₂)_(v) and alkyl groups may be optionally substituted by --O(R²),--S(O)_(m) R², --C(O)OR², --C(O)N(R²)(R²), --SO₂ N(R²)(R²), or--N(R²)C(O)N(R²)(R²), wherein the aryl group is selected from: phenyl,pyridyl, 1H-tetrazolyl, triazolyl, oxadiazolyl, pyrazolyl, thiadiazoyl,and benzimidazol-2-yl, which is optionally substituted with C₁₂ -C₆alkyl, C₃ -C₆ cycloalkyl, amino, or hydroxyl;

X is selected from the group consisting of: hydrogen, ##STR13## andfurther selected from the following group of heterocycles ##STR14##wherein the heterocycle is optionally substituted with a substituentselected from: --N(R²)(R²), --O(R²), C₁ -C₃ alkyl, halogen, andtrifluoromethyl;

Y is selected from the group consisting of: hydrogen, ##STR15## or theirregioisomers whereof where not specified; D is selected from: --N(R⁷)--,--S(O)_(m) --, --C(O)-- and --C(H)(R⁷)--, wherein R⁷ is selected from:--R², --(CH₂)_(q) aryl, --C(O)R², --SO₂ R², --C(O)N(R²)(R²), --C(O)OR²,1-H-tetrazol-5-yl, --SO₂ N(R²)aryl, --SO₂ N(R²)(R²) and the (CH₂)_(q)may be optionally substituted by C₁ -C₄ alkyl, and the R² and aryl maybe optionally further substituted with a substituent selected from:--OR^(2a), --C(O)OR^(2a), --C(O)N(R^(2a))(R^(2a)), halogen, --C₁ -C₄alkyl, and the aryl is selected from of triazolyl, oxadiazolyl,1H-tetrazolyl, and thiadiazolyl;

l is 0, 1 or 2;

m is 0, 1, or 2;

q is 0, 1, 2, 3, or 4;

r is 0, 1, 2, or 3;

t is 0, 1, 2, or 3;

v is 0, 1, or 2;

y is 1 or 2, with the proviso that if E is --O--, y is 2;

and pharmaceutically acceptable salts and individual diastereomersthereof.

The most preferred compounds of the instant invention include compoundsof the formula: ##STR16## wherein B is selected from the groupconsisting of: ##STR17## E' is selected from: --CH═CH--CH₂ --NH₂,--CH═CH--CH(CH₃)--NH₂,

--CH═CH--C(CH₃)₂ --NH₂,

or phenyl substituted with --CH₂ --NH₂, --CH(CH₃)--NH₂, or --C(CH₃)₂--NH₂ ;

and pharmaceutically acceptable salts and individual diastereomersthereof.

The even more preferred compounds of the instant invention includecompounds of the formula: ##STR18## wherein B is selected from the groupconsisting of: ##STR19## and pharmaceutically acceptable salts andindividual diastereomers thereof.

Specific compounds within the instant invention include the following:##STR20## and pharmaceutically acceptable salts and individualdiastereomers thereof where not otherwise specified.

Throughout the instant application, the following abbreviations are usedwith the following meanings:

    ______________________________________    Bu         butyl    Bn         benzyl    BOC, Boc   t-butyloxycarbonyl    BOP        Benzotriazol-1-yloxy tris/dimethylamino)-               phosphonium hexafluorophosphate    calc.      calculated    CBZ, Cbz   Benzyloxycarbonyl    DCC        Dicyclohexylcarbodiimide    DMF        N,N-dimethylformamide    DMAP       4-Dimethylaminopyridine    EDC        1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide               hydrochloride    EI-MS      Electron ion-mass spectroscopy    Et         ethyl    eq.        equivalent(s)    FAB-MS     Fast atom bombardment-mass spectroscopy    HOBT, HOBt Hydroxybenztriazole    HPLC       High pressure liquid chromatography    KHMDS      Potassium bis(trimethylsilyl)amide    LAH        Lithium aluminum hydride    LHMDS      Lithium bis(trimethylsilyl)amide    Me         methyl    MF         Molecular formula    MHz        Megahertz    MPLC       Medium pressure liquid chromatography    NMM        N-Methylmorpholine    NMR        Nuclear Magnetic Resonance    Ph         phenyl    Pr         propyl    prep.      prepared    TFA        Trifluoroacetic acid    THF        Tetrahydrofuran    TLC        Thin layer chromatography    TMS        Tetramethylsilane    ______________________________________

The compounds of the instant invention have at least two asymmetriccenters when B is: ##STR21## and both X and Y are groups other thanhydrogen and are different from each other. Additional asymmetriccenters may be present depending upon the nature of the varioussubstituents on the molecule. Each such asymmetric center willindependently produce two optical isomers and it is intended that all ofthe possible optical isomers and diastereomers in mixture and as pure orpartially purified compounds are included within the ambit of thisinvention. In the case of the asymmetric center which bears the X and Ygroups, in most cases, both R- and S-configurations are consistent withuseful levels of growth hormone secretagogue activity. In additionconfigurations of many of the most preferred compounds of this inventionare ##STR22## indicated. When the carbon atom in Formula I bearing anasterisk is of a defined two diastereomers result according to theabsolute configuration at the carbon atom bearing the X and Y groups.These diastereomers are arbitrarily referred to as diastereomer 1 (d₁)and diastereomer 2 (d2) in this invention and, if desired, theirindependent syntheses or chromatographic separations may be achieved asdescribed herein. Their absolute stereochemistry may be determined bythe x-ray crystallography of crystalline products or crystallineintermediates which are derivatized, if necessary, with a reagentcontaining an asymmetric center of known absolute configuration.

The instant compounds are generally isolated in the form of theirpharmaceutically acceptable acid addition salts, such as the saltsderived from using inorganic and organic acids. Examples of such acidsare hydrochloric, nitric, sulfuric, phosphoric, formic, acetic,trifluoroacetic, propionic, maleic, succinic, malonic, methane sulfonicand the like. In addition, certain compounds containing an acidicfunction such as a carboxy can be isolated in the form of theirinorganic salt in which the counterion can be selected from sodium,potassium, lithium, calcium, magnesium and the like, as well as fromorganic bases.

The preparation of compounds of Formula I of the present invention maybe carried out in sequential or convergent synthetic routes. Synthesesdetailing the preparation of the compounds of Formula I in a sequentialmanner are presented in the following reaction schemes.

The phrase "standard peptide coupling reaction conditions" is usedrepeatedly here, and it means coupling a carboxylic acid with an amineusing an acid activating agent such as EDC, DCC, and BOP in a inertsolvent such as dichloromethane in the presence of a catalyst such asHOBT. The uses of protective groups for amine and carboxylic acid tofacilitate the desired reaction and minimize undesired reactions arewell documented. Conditions required to remove protecting groups whichmay be present and can be found in Greene, T, and Wuts, P. G. M.,Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., NewYork, N.Y. 1991. CBZ and BOC were used extensively in the synthesis, andtheir removal conditions are known to those skilled in the art. Forexample, removal of CBZ groups can be achieved by a number of methodsknown in the art; for example, catalytic hydrogenation with hydrogen inthe presence of a nobel metal or its oxide such as palladium onactivated carbon in a protic solvent such as ethanol. In cases wherecatalytic hydrogenation is contraindicated by the presence of otherpotentially reactive functionality, removal of CBZ groups can also beachieved by treatment with a solution of hydrogen bromide in aceticacid, or by treatment with a mixture of TFA and dimethylsulfide. Removalof BOC protecting groups is carried out in a solvent such as methylenechloride or methanol or ethyl acetate, with a strong acid, such astrifluoroacetic acid or hydrochloric acid or hydrogen chloride gas.

The protected amino acid derivatives 1 are, in many cases, commerciallyavailable, where the protecting group L is, for example, BOC or CBZgroups. Other protected amino acid derivatives 1 can be prepared byliterature methods (Williams, R. M. Synthesis of Optically Activeα-Amino Acids, Pergamon Press: Oxford, 1989). Many of the piperidines,pyrrolidines, and hexahydro-1H-azepines of Formula 2 are eithercommercially available or known in the literature and others can beprepared following literature methods described for analogous compounds.Some of these methods are illustrated in the subsequent schemes. Theskills required in carrying out the reaction and purification of theresulting reaction products are known to those in the art. Purificationprocedures includes crystallization, normal phase or reverse phasechromatography. ##STR23##

Intermediates of Formula 3 may be synthesized as described in Scheme 1.Coupling of amine of Formula 2, whose preparations are described laterif they are not commercially available, to protected amino acids ofFormula 1, wherein L is a suitable protecting group, is convenientlycarried out under standard peptide coupling conditions. ##STR24##

Conversion of 3 to intermediate 4 may be carried out as illustrated inScheme 2 by removal of the protecting group L (CBZ, BOC, etc.) ##STR25##

Intermediates of Formula I may be prepared as shown in Scheme 3 bycoupling intermediates of Formula 4 to protected amino acids of Formula5 under the standard peptide-type coupling reaction conditions. Theamino acids 5 are either commercially available or can be synthesized byroutine methods. ##STR26##

As shown in Scheme 4, if R⁴ or R⁵ is a hydrogen then the protected aminoacids 6 are employed in the coupling reaction wherein L is a protectinggroup as defined above. The removal of L to afford I can be carried outas noted above. ##STR27##

Compounds of Formula I wherein R⁴ and/or R⁵ is a hydrogen may be furtherelaborated to new Compounds I which are substituted on the amino groupas depicted in Scheme 5. Reductive alkylation of I with an aldehyde iscarried out under conditions known in the art; for example, by catalytichydrogenation with hydrogen in the presence of platinum, palladium, ornickel catalysts or with chemical reducing agents such as sodiumcyanoborohydride in a protic solvent such as methanol or ethanol in thepresent of catalytic amount of acid. Alternatively, a similartransformation can be accomplished via an epoxide opening reaction.

The compounds of general Formula I of the present invention may also beprepared in a convergent manner as described in Scheme 6. Intermediatesof Formula 7 can be synthesized by well documented methods in theliterature. Elaboration of 7 to compounds of Formula 1 can beaccomplished as shown in Scheme 6 by coupling intermediates of Formula 7to amino acids of Formula 6 under standard peptide coupling reactionconditions. ##STR28##

Removal of the protecting group L can be accomplished by well documentedmethods and amines BH of Formula 2 can be coupled to the correspondingacid under standard peptide-type coupling conditions to give compoundsof Formula I. When R⁴ and/or R⁵ is H, substituted alkyl groups may beoptionally added to the nitrogen atom as described in Scheme 5.

In the following Schemes preparartions of amines BH of Formula 3 aredescribed. ##STR29##

3-Monosubstituted piperidines of formula 13 can be prepared by thereduction of pyridine derivatives or their salts by hydrogenation in asuitable organic solvent such as water, acetic acid, alcohol, e.g.ethanol, or their mixture, in the presence of a noble metal catalystsuch as platinum or an oxide thereof on a support such as activatedcarbon, and conveniently at room temperature and atmospheric pressure orunder elevated temperature and pressure. 3-Monosubstituted piperidinescan also be prepared by modification of the X or Y moiety of theexisting 3-monosubstituted piperidines. ##STR30##

3-Monosubstituted pyrrolidines are commercially available or can beconveniently prepared by literature procedures. Shown in Scheme 8 is anexample of the preparation of these compounds viapyrrolidine-3-carboxylic acid ester. The commercially available compoundmethyl 1-benzyl-4-oxo-3-pyrrolidinecarboxylate is reduced by borane (J.Chem. Soc., 24, 1618-1619). Removal of the benzyl group by catalytichydrogenolysis followed by ester exchange in an appropriate alcoholmedium such as ethyl alcohol in the presence of acid gave the compound13b. The ester functionality may be further modified throughconventional chemistry to other groups as defined by X.3-Monosubstituted pyrrolidines may also be prepared by catalytichydrogenation of 3-substituted pyrroles. ##STR31##

Hexahydro-1H-azepines are commercially available or may be prepared bythe literature procedure. Hexahydro-1H-azepine-3-carboxylic acid(Krogsgaard-Larsen, P. et al., Acta. Chem. Scand., B32, 327, (1978)) isesterified in an alcohol solvent in the presence of acid. The esterfunctionality may be further modified through conventional chemistry toother groups within the definition of X. ##STR32##

Illustrated in Scheme 10 is a general way to prepare di-substitutedpiperidines, pyrrolidines, and hexahydro-1H-azepines. Compounds ofFormula 13 wherein X is an electron withdrawing group such as --CN,--CO₂ R₈, where R₈ is alkyl, aryl, and (C₁ -C₄ alkyl)aryl are knowncompounds or may be prepared by methods analogous to those used for thepreparation of such known compounds. The secondary amine of compounds ofFormula 13 may be first protected by a protecting group L such as BOCand CBZ using the conventional techniques. Introduction of the Ysubstitution can be achieved by first reacting compounds of Formula 14with a strong base such as lithium bis(trimethylsilyl)amide, lithiumdiisopropylarnide following by addition of alkylating or acylatingreagents such as alkyl halides, aryl alkyl halides, acyl halides, andhaloformates in a inert solvent such as THF at temperatures from -100°to room temperature. Thio derivatives where the sulfur is attacheddirectly to an alkyl or an aryl group can be prepared similarly byreacting with a disulfide. The halides used in these reactions areeither commercially available or known compounds in the literature ormay be prepared by methods analogous to those used for the preparationof known compounds. The protecting group L in compounds of formula 15may be removed with conventional chemistry to give compounds of Formula2. ##STR33##

Alternative ways of preparing compounds of Formula 2 includeconstruction of the ring itself (Jacoby, R. L. et al, J. Med. Chem., 17,453-455, (1974)). Alkylation of the cyanoacetates of general formula 16,which are commercially available or may be prepared from literatureprocedures, with alkyl dihalides such as 1-bromo-2-chloroethane or1-bromo-3-chloropropane yields the chloride 17. Reduction of thenitrites 17 by borane or by hydrogenation using Raney Ni as a catalystgives the corresponding primary amines, which upon refluxing in ethanolto give compounds of Formula 2a. ##STR34##

Alternatively, the cyanoacetates of general formula 16 may be alkylatedwith an ethoxycarbonylalkyl bromide or reacted with ethyl acrylate togive compounds of Formula 18. Reduction of the nitrites 18 by borane orby hydrogenation using Raney Ni as a catalyst gives the correspondingprimary amines, which upon refluxing in ethanol gives lactam 19.Reduction of the lactam 19 by borane gives compounds of Formula 2a.##STR35##

Alternatively, a malonate of general formula 20 may be alkylated withcyanoalkyl bromide or can be reacted with acrylonitrile to formcompounds of formula 21. Reduction of the nitrites 21 by borane or byhydrogenation using Raney Ni as a catalyst gives the correspondingprimary amines, which upon refluxing in ethanol gives lactam 22.Reduction of the lactam 22 by borane gives compounds of formula 2a.##STR36##

The X, Y functionalities in compounds of general structure 15 may befurther elaborated to groups not accessible by direct alkylation. Forexample in Compound 15 when X=CO₂ Et the ester (provided that this isthe only ester group in the molecule) can be saponified to thecarboxylic acid, which can be further derivatized to amides or otheresters. The carboxylic acid can be converted into its next higherhomologue, or to a derivative of the homologous acid, such as amide orester by an Arndt-Eistert reaction. Alternatively, the ester can bedirectly homologated by the protocol using ynolate anions described byC. J. Kowalski and R. E. Reddy in J. Org. Chem., 57, 7194-7208 (1992).The resulting acid and/or ester may be converted to the next higherhomologue, and so on and so forth. The protecting group L may be removedthrough conventional chemistry. ##STR37##

The ester in 15a may be reduced to an alcohol 18 in a suitable solventsuch as THF or ether with a reducing agent such as DIB AL-H andconveniently carried out at temperatures from -100° C. to 0° C. Thealcohol may be acylated to Compound 19 in a suitable solvent such asdichioromethane using an acyl halide or acid anhydride in the presenceof a base such as triethyl amine (TEA). The hydroxy group in 18 may alsobe converted to a good leaving group such as mesylate and displaced by anucleophile such as cyanide, a thiol or an azide. Reduction of the azidein compounds of Formula 20 to an amine 21 can be achieved byhydrogenation in the presence of a noble metal such as palladium or itsoxide or Raney nickel in a protic solvent such as ethanol. The nitrilecan be reduced to afford the homologous amine. The amine of Formula 21may be further elaborated to amides, ureas sulfonamides as defined by Xthrough conventional chemistry. The protecting group L may be removedthrough conventional chemistry. ##STR38##

In cases where oxygen is directly attached to the ring, a convenientmethod involves the addition reaction by an activated form of an alkyl,aryl, alkylaryl group, such as lithium reagent, Grignard reagents, andthe like with a ketone of general formula 28, which is commerciallyavailable. Further derivatization of the resulting hydroxy group byacylation, sulfonylation, alkylation, and the like gives compounds asdefined by Y or X through conventional chemistry. Removal of the benzylprotective group may be carried out under the usual conditions to givecompounds of general formula 2b. Shown in Scheme 16 is a general exampleof acylations. ##STR39##

In cases where a nitrogen-substituted group is directly attached to thering, a convenient method is to use the Curtius rearrangement on theacid 23 to afford the isocyanate 31. Addition of amines or alcohols giveureas or carbamates respectively which can be deprotected to remove L togive special cases of compounds of formula 2. Conversion of theisocyanate to amine by hydrolysis gives compound 32. Furtherderivatization of the resulting amine group by acylation, sulfonylation,alkylation, and the like to give compounds as defined by Y or X can bedone through conventional chemistry. Removal of the protective group Lmay be carried out under the usual conditions to give compounds ofgeneral formula 2c. Shown in Scheme 17 is a general example ofacylations. ##STR40##

For compounds that are not readily obtainable by direct alkylation asshown in Scheme 10, modifications of easily obtainable compounds ofgeneral formula 15 may be conducted to achieve the desired substitutionthrough conventional chemistry. For example, compounds with Y beinghydroxybenzyl may be prepared by demethylation of the correspondingcompound wherein Y is methoxybenzyl. Similarly, compounds with Y beingaminobenzyl may be prepared by reduction of the corresponding compoundwherein Y is nitrobenzyl. Shown in Scheme 18 is an example of aprocedure that uses nitrile as a starting point for the preparation ofcompounds with different substitutions. Removal of the protective groupL gives compounds of general formula 2 as described in Scheme 10.

Compounds of the general formula 2 prepared in this way are racemic whenX and Y are not identical. Resolution of the two enatiomers can beconveniently achieved by classical crystallization methods by using achiral acid such as L- or D-tartaric acid, (+) or (-)-10-camphorsulfonicacid in a suitable solvent such as acetone, water, alcohol, ether,acetate or their mixture. Alternatively, the racemic amine 2 can bereacted with a chiral auxiliary such as (R) or (S)--O-acetylmandelicacid followed by chromatographic separation of the two diastereomers,and removal of the chiral auxiliary by hydrolysis. Alternativelyasymmetric alkylation can also be utilized for the synthesis ofoptically active intermediate by introducing a removable chiralauxiliary in X or in place of L with subsequent chromatographicseparation of diastereomers.

In cases where a sulfide is present in the molecule, it may be oxidizedto a sulfoxide or to a sulfone with oxidizing agents such as sodiumperiodate, m-chloroperbenzoic acid or Oxone® in an solvent such asdichloromethane, alcohol or water or their mixtures.

The compounds of the present invention may also be prepared from avariety of substituted natural and unnatural amino acids of formulas 46.The preparation of many of these acids is described in U.S. Pat. No.5,206,237. The preparation of these intermediates in racemic form isaccomplished by classical methods familiar to those skilled in the art(Williams, R. M. "Synthesis of Optically Active a-Amino Acids" PergamonPress: Oxford, 1989; Vol. 7). Several methods exist to resolve ##STR41##(DL)-amino acids. One of the common methods is to resolve amino orcarboxyl protected intermediates by crystallization of salts derivedfrom optically active acids or amines. Alternatively, the amino group ofcarboxyl protected intermediates may be coupled to optically activeacids by using chemistry described earlier. Separation of the individualdiastereomers either by chromatographic techniques or by crystallizationfollowed by hydrolysis of the chiral amide furnishes resolved aminoacids. Similarly, amino protected intermediates may be converted to amixture of chiral diastereomeric esters and amides. Separation of themixture using methods described above and hydrolysis of the individualdiastereomers provides (D) and (L) amino acids. Finally, an enzymaticmethod to resolve N-acetyl derivatives of (DL)-amino acids has beenreported by Whitesides and coworkers in J. Am. Chem. Soc. 1989, 111,6354-6364.

When it is desirable to synthesize these intermediates in optically pureform, established methods include: (1) asymmetric electrophilicamination of chiral enolates (J. Am. Chem. Soc. 1986, 108 6394-6395,6395-6397, and 6397-6399), (2) asymmetric nucleophilic amination ofoptically active carbonyl derivatives, (J. Am. Chem. Soc. 1992, 114,1906; Tetrahedron Lett. 1987, 28, 32), (3) diastereoselective alkylationof chiral glycine enolate synthons (J. Am. Chem. Soc. 1991, 113, 9276;J. Org. Chem. 1989, 54, 3916), (4) diastereoselective nucleophilicaddition to a chiral electrophilic glycinate synthon (J. Am. Chem. Soc.1986, 108, 1103), (5) asymmetric hydrogenation of prochiral dehydroaminoacid derivatives ("Asymmetric Synthesis, Chiral Catalysis; Morrison, J.D., Ed; Academic Press: Orlando, Fla., 1985; Vol 5), and (6) enzymaticsyntheses (Angew. Chem. Int. Ed. Engl. 1978, 17, 176). ##STR42##

For example, alkylation of the enolate of diphenyloxazinone 47 (J. Am.Chem. Soc. 1991, 113, 9276) with cinnamyl bromide in the presence ofsodium bis(trimethylsilyl)amide proceeds smoothly to afford 48 which isconverted into the desired (D)-2-amino-5-phenylpentanoic acid 49 byremoving the N-t-butyloxycarbonyl group with trifluoroacetic acid andhydrogenation over a PdCl₂ catalyst (Scheme 19). ##STR43##

Intermediates of formula 46 which are O-benzyl-(D)-serine derivatives 51are conveniently prepared from suitably substituted benzyl halides andN-protected-(D)-serine 50. The protecting group L is conveniently a BOCor a CBZ group. Benzylation of 64 can be achieved by a number of methodswell known in the literature including deprotonation with twoequivalents of sodium hydride in an inert solvent such as DMF followedby treatment with one equivalent of a variety of benzyl halides(Synthesis 1989, 36) as shown in Scheme 20.

The O-alkyl-(D)-serine derivatives may also be prepared using analkylation protocol. Other methods that could be utilized to prepare(D)-serine derivatives of formula 51 include the acid catalyzedbenzylation of carboxyl protected intermediates derived from 50 withreagents of formula ArCH₂ OC(═NH)CCl₃ (O. Yonemitsu et al., Chem. Pharm.Bull. 1988, 36, 4244). Alternatively, alkylation of the chiral gylcineenolates (J. Am. Chem. Soc. 1991, 113, 9276; J. Org. Chem. 1989, 54,3916) with ArCH₂ OCH₂ X where X is a leaving group affords 51. Inaddition D,L-O-aryl(alkyl)serines may be prepared and resolved bymethods described above.

The spiro piperidines of formula 52 may be prepared by a number ofmethods, including the syntheses described below. ##STR44##

As shown in Scheme 21, the spiropiperidine of formula 43, wherein L is adefined protecting group, is synthesized by methods that are known inthe literature (for example H. Ong et al J. Med. Chem. 1983, 23,981-986). The indoline nitrogen of 54, wherein L is a protecting groupsuch as methyl or benzyl, can be reacted by with a variety ofelectrophiles to yield spiro piperidines of formula 54, wherein Rg canbe a variety of functionalities. Compound 54 can be reacted with, forexample, isocyanates in an inert solvent like dichloromethane to yieldurea derivatives, chloroformates in an inert solvent such asdichloromethane to yield carbamates, acid chlorides, anhydrides, or acylimidazoles to generate amides, sulfonyl chlorides to generatesulfonamides, sulfamyl chlorides to yield sulfamides. Also, the indolinenitrogen of 53 can be reductively alkylated with aldehydes withconditions known in the art. When the aldehyde used in the reductiveamination reaction is a protected glyoxylic acid of structure HCOCOOM,wherein M is a defined protecting group, M can be removed from theproduct and further derivatized. Alternatively, 53 can be reacted withepoxides to produce 53, wherein R⁹ is β-hydroxy-substituted alkyl orarylalkyl groups. The indoline 53 can also be transformed to compoundsof formula 54, wherein R⁹ =phenyl or substituted phenyl, heteroaryl orsubstituted heteroaryl, by carrying out the reacting 53 with a fluorophenyl or fluoro heteroaryl reagent. This chemistry is detailed by H.Ong et al J. Med. Chem. 1983, 23, 981-986. ##STR45##

The Spiro piperidine intermediate 54 (L=Me or Bn), wherein R⁷ ishydrogen or most of the derivatives described above, can be demethylatedor debenzylated to produce 55, wherein R⁹ is hydrogen or most of thederivatives described above, as shown in Scheme 22. For compounds offormula 54, wherein L=Me, demethylation can be carried out by a numbermethods familiar those skilled in the art. For example, demethylation of54 be accomplished by reacting it with cyanogen bromide and potassiumcarbonate in an inert solvent solvent such as dichloromethane to yield acyanamide which can reduced to give 55 by treatment with lithiumaluminum hydride in refluxing tetrahydrofuran, refluxing strong acidlike aqueous hydrochloric acid, or with Grignard reagents like methylmagnesium bromide. Alternatively, demethylation of 54 can be effectedwith the ACE-Cl method as described in R. Olofson et al. J. Org. Chem.1984, 49, 2795 and references therein. For intermediates of formula 54,wherein L=Bn, removal of benzyl group can be accomplished by reductivemethods including hydrogenation in the presence of platinum or palladiumcatalyst in a protic solvent like methanol. Alternatively, debenzylationof 54, L=Bn, can be effected with the ACE-Cl method as described in R.Olofson et al. J. Org. Chem. 1984, 49, 2795 and references therein.##STR46##

The spiro heterocyclic compounds of formula 56 can be prepared by anumber of methods, including the syntheses as described in Scheme 23.Allylic oxidation of the protected piperidine 58 is accomplished byclassical methods familiar to those skilled in the art (Rabjohn, N. Org.React. 1976, 24, 261). The resulting allylic alcohol is treated withthionyl chloride in an inert solvent such as benzene to provide thecorresponding chloride 59. When D=O or S, the alkylation is carried outin DMF or acetone as solvent with potassium carbonate as a base, andwhen D=NR⁷ (R⁷ =H, alkyl, aryl, acyl, sulfonyl, carbamate) the reactionis carried out with sodium hydride as a base in an inert solvent such asTHF to afford the cyclization precursor 60. When L is a definedprotecting group, compound 60 can be cyclized by a number methodsfamiliar to those skilled in the art. For example, cyclization of 60 canbe accomplished by reaction with tributyltin hydride (Curran, D. P.Synthesis 1988, 417 and 489) in an inert solvent such as benzene toyield 57. Alternatively, compound 57 (D=NR₉) can be prepared by themethod shown in Schemes 24 and 25. ##STR47## D=S(O)_(m) m=1,2

As shown in Scheme 24, when D=S, compound 57 can be oxidized to thesulfoxide 57 (n=1) and the sulfone 57 (n=2) by many oxidizing agents.For example, sodium periodate is often used for the synthesis ofsulfoxides and Oxone is used for the synthesis of sulfones. Removal ofthe protecting group provides the amine 56 which then can beincorporated into a growth hormone secretagogue via the chemistrydetaileds in Scheme 1 and 8 shown above which utilize genericintermediate 2.

Compounds of formula I wherein R⁴ and R⁵ are each hydrogen can befurther elaborated by reductive alkylation with an aldehyde by theaforementioned procedures or by alkylations such as by reaction withvarious epoxides. The products, obtained as hydrochloride ortrifluoroacetate salts, are conveniently purified by reverse phase highperformance liquid chromatogrphy (HPLC) or by recrystallization.##STR48##

Homologation of the spiroindanone 64 provides easy access tospiroindanyl intermediates containing acid and ester groups. Thischemistry is described in Scheme 26. Treatment of 64 with a base in aninert solvent such as THF followed by the addition of a triflating agentprovides the enol triflate. Carboxylation of the enol triflate accordingto the procedure of Cacchi, S. Tetrahedron Letters, 1985, 1109-1112provides the ester 66. The protecting group can then be removed asdescribed above and the resulting amine can be incorporated into thesubject compound via the chemistry depicted in Schemes 1 and 8. Acompound containing an acid function is readily available viasaponification of the ester group as the final step of the synthesis.

Saponification of the ester of 66 provides an acid which can beconveniently derivatized as for example reaction with an amine in thepresence of a coupling agent such as EDC gives amides which can then beincorporated into final compounds following the chemistry detailed inSchemes 1 and 8.

Hydrogenation of 66 using a palladium catalyst in an inert solventprovides the saturated compounds which can then either be derivatized asabove or carried on to the final products via the chemistry described inSchemes 1 and 8. The ester may also be reduced to a primary alcohol withLAH and to a aldehyde with DIBALH. Reductive alkylation of the aldehydewith ammonium acetate and sodium cyanoborohydride affords an aminomethyl analog. These hydroxymethyl and aminomethyl analogs may then befurther reacted to afford additional growth hormone secretagogues of thegeneral formula I. Chiral acids are available by a variety of methodsknown to those skilled in the art including asymmetric catalytichydrogenation and resolution of a pair of diastereomeric salts formed byreaction with a chiral amine such as D or L α-methylbenzylamine. Theabsolute stereochemistry can be determined in a number of ways includingX-ray crystallography of a suitable crystalline derivative.

Spiroindane intermediates, for incorporation into growth hormonesecretagogues, can be further elaborated in the benzylic position by thechemistry detailed in the following schemes. ##STR49##

As depicted in Scheme 27, homologs of ester 69 can be convientlyprepared by a variety of methods known to those skilled in the artigncluding the displacement of an activated alcohol such as tosylate 70by a malonate nucleophile followed by decarboxylation or a cupratereaction followed by the adjustment of the chain length or oxidationstate as appropiate. ##STR50##

Alternatively the reaction of spiroindanone 64 with Wittig or Emmonsreagents also provides access to homologs of ester 69. The chemistry isdescribed in Scheme 28. Treatment of triethylphosphonoacetate with abase in an inert solvent such as THF followed by the addition of ketone64 provides the unsaturated ester 75. Hydrogenation of 75 using apalladium catalyst in an inert solvent provides the saturated ester 76.The protecting group can then be removed as described above and theresulting amine can be incorporated into a final compound via thechemistry described in Schemes 1 and 8. A secretagogue containing anacid function can be obtained via saponification of the ester functionas the final step of the synthesis.

Chiral esters and acids are available by a variety of methods known tothose skilled in the art including asymmetric catalytic hydrogenation,chomatographic resolution of a pair of diasteromers, and viacrystallization of salts formed from chiral amines such as D orL-α-methylbenzylamine. The absolute stereochemistry can be determined ina number of ways including X-ray crystallography of a suitablecrystalline derivative.

The ester can be reduced to an alcohol by treatment with LAH and to analdehyde with DIBALH. Reductive alkylation of the aldehyde with ammoniumacetate and sodium cyanoborohydride affords an amino methyl analog.These hydroxymethyl and aminomethyl analogs may then be further reactedto afford additional growth hormone secretagogues of the general formula1.

Saponification of ester 44 provides an acid which can be convientlyderivatized as for example reaction with an amine in the presence of acoupling reagent such as EDC gives amides which can be incorporated intoa secretagogue as detailed in Schemes 1 and 8.

Homologation of ester 44 is possible using a variety of methods known tothose skilled in the art including the method described in J. Org. Chem.1992, 57 7194-7208. ##STR51##

As shown in Scheme 29, a variety of acid equivalents can also beincorporated into the spiroindane intermediates for exampleacylsulfonamides are readily available from acids such as 67 and 72.Treatment of the spiroindane acid with a base in an inert solvent suchas THF followed by the addition of oxalyl chloride provides an acidchloride which is then treated with a sodium salt of a sulfonamide. Theprotecting group can then be removed using chemistry described above andthe resulting amine can be incorporated into a final compound usingchemistry depicted in Schemes 1 and 8. ##STR52##

As shown in Scheme 30, tetrazole spiroindane intermediates are availablefrom nitrites of both the shorter and longer homolog series. For examplethe reaction of enol triflate 65 with a cyanide anion and a palladiumcatalyst in the presence of an inert solvent such as toluene providesthe unsaturated nitrile which can be converted into the tetrazole byreaction with trimethylstannyl azide in an inert solvent at elevatedtemperatures. Reduction of the indene double bond in 78 and 79 withcatalysts such as Pd/C in ethanol affords the corresponding saturatedanalogs. ##STR53##

As shown in Scheme 31, esters such as 69 can be conviently acylated oralkylated next to the ester function by treatment with a variety ofbases and alkylating or acylating agents. For example reaction of 69with potassium bis(trimethyl-silylamide) in an inert solvent such as THFfollowed by the addition of ethyl chloroformate provides 80 in goodyield. Removal of the protecting group and incorporation into thesubject compounds can be accomplished as described above. ##STR54##

As shown in Scheme 32, further substitution at the benzylic position ofthe spiroindanes is readily carried out via the tosylate of the alcohol.Displacement of the tosylate with a variety of nucleophiles is possible.For example treatment of tosylate 70 with sodium thiomethoxide in DMSOprovides the sulfide 81. The protecting group can be removed as aboveand the resulting amine can be incorporated into the final compoundemploying chemistry described in Schemes 1 and 8. Alternatively thesulfide can be oxidized to the sulfoxide or sulfone by treatment withthe appropriate oxidizing agent prior to deprotection or as the finalstep in the synthesis. ##STR55##

As shown in Scheme 33, the incorporation of aryl and heteroaryl groupsinto the benzylic position of spiroindanes is most coveniently carriedout via the enol triflate 65. Palladium catalysed reaction of the enoltriflate with a variety of aryl or heteroarylstannanes in an inertsolvent such as toluene provides the desired intermediates. For example2-trimethylstannyl-pyridine reacts with 65 in the presence of acatalytic amount of tetrakis(triphenylphosphene)palladium in toluene atrefux to give the coupled product 82. Alternativiely the enol triflate65 can be converted into the vinyl stannane 83 by reaction withhexamethylditin and a palladium catalyst in an inert solvent such astoluene. The vinyl stannane can then be coupled with a variety of arylor hetero aryl bromides or triflates, for example coupling to2-bromo-3-carbo-methoxypyridine provides 84. The protecting group L canbe removed from the coupled products using chemistry described above andthe resulting amine can be included in the final compound as describedin Schemes 1 and 8.

In the following Schemes 34-36 syntheses of amino acids of Formula 6 aredescribed. Various methods are well documented in the art to prepareprotected amino acids of formula 85. ##STR56##

As shown in Scheme 34, benzoic acids esters of formula 86 are reducedwith Raney nickel in ethanol in the presence of ammonia to provide thecorresponding benzylamine derivative 87. The amino group is protected asits Boc or CBZ derivative and the ester group is hydrolyzed to giveprotected amino acids of formula 85. ##STR57##

As shown in Scheme 35, other methods of the synthesis of 85 originatefrom benzyl halides of formula 88. The halide is displaced with sodiumazide usually in a polar aprotic solvent such as DMF or DMSO to give thecorresponding azide that is reduced with triphenylphosphine in THF-waterto give the amine derivative that is converted to acids of formula 85 asdescribed above. ##STR58##

Olefinic amino acids of formula 89 may be prepared as shown in Scheme36. The Boc-aminoisobutyric acid methyl ester 90 is reduced to thecorresponding aldehyde derivative 91 with the use of diisobutylaluminumhydride in a aprotic solvent such as THF or dichloromethane.Alternatively, the commercially available acid of 90 may be reduced withdiborane to the alcohol and reduced up to the aldehyde 91 by using Swernoxidation protocol. A Homer-Emmons condensation of 91 withtriethylphosphonoacetate by using a base like potassium t-butoxide in anaprotic solvent provides the corresponding unsaturated aester that canbe hydrolyzed under standard conditions to protected amino acid offormula 89.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts.

The utility of the compounds of the present invention as growth hormonesecretagogues may be demonstrated by methodology known in the art, suchas an assay disclosed by Smith, et al., Science, 260, 1640-1643 (1993)(see text of FIG. 2 therein). In particular, all of the compoundsprepared in the following examples had activity as growth hormonesecretagogues in the aforementioned assay. Such a result is indicativeof the intrinsic activity of the present compounds as growth hormonesecretagogues.

The growth hormone releasing compounds of Formula I are useful in vitroas unique tools for understanding how growth hormone secretion isregulated at the pituitary level. This includes use in the evaluation ofmany factors thought or known to influence growth hormone secretion suchas age, sex, nutritional factors, glucose, amino acids, fatty acids, aswell as fasting and non-fasting states. In addition, the compounds ofthis invention can be used in the evaluation of how other hormonesmodify growth hormone releasing activity. For example, it has alreadybeen established that somatostatin inhibits growth hormone release.Other hormones that are important and in need of study as to theireffect on growth hormone release include the gonadal hormones, e.g.,testosterone, estradiol, and progesterone; the adrenal hormones, e.g.,cortisol and other corticoids, epinephrine and norepinephrine; thepancreatic and gastrointestinal hormones, e.g., insulin, glucagon,gastrin, secretin; the vasoactive peptides, e.g., bombesin, theneurokinins; and the thyroid hormones, e.g., thyroxine andtriiodothyronine. The compounds of Formula I can also be employed toinvestigate the possible negative or positive feedback effects of someof the pituitary hormones, e.g., growth hormone and endorphin peptides,on the pituitary to modify growth hormone release. Of particularscientific importance is the use of these compounds to elucidate thesubcellular mechanisms mediating the release of growth hormone.

The compounds of Formula I can be administered to animals, includingman, to release growth hormone in vivo. For example, the compounds canbe administered to commercially important animals such as swine, cattle,sheep and the like to accelerate and increase their rate and extent ofgrowth, to improve feed efficiency and to increase milk production insuch animals. In addition, these compounds can be administered to humansin vivo as a diagnostic tool to directly determine whether the pituitaryis capable of releasing growth hormone. For example, the compounds ofFormula I can be administered in vivo to children. Serum samples takenbefore and after such administration can be assayed for growth hormone.Comparison of the amounts of growth hormone in each of these sampleswould be a means for directly determining the ability of the patient'spituitary to release growth hormone.

Accordingly, the present invention includes within its scopepharmaceutical compositions comprising, as an active ingredient, atleast one of the compounds of Formula I in association with apharmaceutical carrier or diluent. Optionally, the active ingredient ofthe pharmaceutical compositions can comprise an anabolic agent inaddition to at least one of the compounds of Formula I or anothercomposition which exhibits a different activity, e.g., an antibioticgrowth permittant or an agent to treat osteoporosis or in combinationwith a corticosteroid to minimize the latter's catabolic side effects orwith other pharmaceutically active materials wherein the combinationenhances efficacy and minimizes side effects.

Growth promoting and anabolic agents include, but are not limited to,TRH, diethylstilbesterol, amino acids, estrogens, β-agonists,theophylline, anabolic steroids, enkephalins, E series prostaglandins,retinoic acid, compounds disclosed in U.S. Pat. No. 3,239,345, e.g.,zeranol, and compounds disclosed in U.S. Pat. No. 4,036,979, e.g.,sulbenox. or peptides disclosed in U.S. Pat. No. 4,411,890.

A still further use of the compounds of this invention is in combinationwith other growth hormone secretagogues such as the growth hormonereleasing peptides GHRP-6, GHRP-1 as described in U.S. Pat. Nos.4,411,890 and publications WO 89/07110, WO 89/07111 and B-HT920 as wellas hexarelin and GHRP-2 as described in WO 93/04081 or growth hormonereleasing hormone (GHRH, also designated GRF) and its analogs or growthhormone and its analogs or somatomedins including IGF-1 and IGF-2 orα-adrenergic agonists such as clonidine or serotonin 5HTID agonists suchas sumitriptan or agents which inhibit somatostatin or its release suchas physostigmine and pyridostigmine. In particular, the compounds ofthis invention may be used in combination with growth hormone releasingfactor, an analog of growth hormone releasing factor, IGF-1, or IGF-2.For example, a compound of the present invention may be used incombination with IGF-1 for the treatment or prevention of obesity. Inaddition, a compound of this invention may be employed in conjunctionwith retinoic acid to improve the condition of musculature and skin thatresults from intrinsic aging.

The present invention is further directed to a method for themanufacture of a medicament for stimulating the release of growthhormone in humans and animals comprising combining a compound of thepresent invention with a pharmaceutical carrier or diluent.

As is well known to those skilled in the art, the known and potentialuses of growth hormone are varied and multitudinous. Thus, theadministration of the compounds of this invention for purposes ofstimulating the release of endogenous growth hormone can have the sameeffects or uses as growth hormone itself. These varied uses may besummarized as follows: stimulating growth hormone release in elderlyhumans; treating growth hormone deficient adults; prevention ofcatabolic side effects of glucocorticoids; treatment of osteoporosis;stimulation of the immune system, acceleration of wound healing;accelerating bone fracture repair; treatment of growth retardation;treating acute or chronic renal failure or insufficiency; treatment ofphysiological short stature, including growth hormone deficientchildren; treating short stature associated with chronic illness;treating obesity and growth retardation associated with obesity;treating growth retardation associated with Prader-Willi syndrome andTurner's syndrome; accelerating the recovery and reducinghospitalization of burn patients or following major surgery such asgastrointestinal surgery; treatment of intrauterine growth retardation,and skeletal dysplasia; treatment of hypercortisonism and Cushing'ssyndrome; treatment of peripheral neuropathies; replacement of growthhormone in stressed patients; treatment of osteochondrody-splasias,Noonans syndrome, sleep disorders, schizophrenia, depression,Alzheimer's disease, delayed wound healing, and psychosocialdeprivation; treatment of pulmonary dysfunction and ventilatordependency; prevention or treatment of congestive heart failure,improving pulmonary function, restoring systolic and diastolic function,increasing myocardial contractility, decreasing peripheral totalvascular resistance, diminishing or preventing loss of body weight andenhancing recovery following congestive heart failure; increasingappetite; attenuation of protein catabolic response after a majoroperation; treating malabsorption syndromes; reducing cachexia andprotein loss due to chronic illness such as cancer or AIDS; acceleratingweight gain and protein accretion in patients on TPN (total parenteralnutrition); treatment of hyperinsulinemia including nesidioblastosis;adjuvant treatment for ovulation induction and to prevent and treatgastric and duodenal ulcers; stimulation of thymic development andpreventtion of the age-related decline of thymic function; adjunctivetherapy for patients on chronic hemodialysis; treatment ofimmunosuppressed patients and to enhance antibody response followingvaccination; increasing the total lymphocyte count of a human, inparticular, increasing the T₄ /T₈ -cell ratio in a human with adepressed T₄ /T₈ -cell ratio resulting, for example, from infection,such as bacterial or viral infection, especially infection with thehuman immunodeficiency virus; treatment of syndromes manifested bynon-restorative sleep and musculoskeletal pain, including fibromyalgiasyndrome or chronic fatigue syndrome; improvement in muscle strength,mobility, maintenance of skin thickness, metabolic homeostasis, renalhemeostasis in the frail elderly; stimulation of osteoblasts, boneremodelling, and cartilage growth; prevention and treatment ofcongestive heart failure; protection of cardiac structure and/or cardiacfunction; enhancing of recovery of a mammal following congestive heartfailure; enhancing and/or improving sleep quality as well as theprevention and treatment of sleep disturbances; enhancing or improvingsleep quality by increasing sleep efficiency and augmenting sleepmaintenance; prevention and treatment of mood disorders, in particulardepression; improving mood and subjective well being in a subjectsuffering from depression; stimulation of the immune system in companionanimals and treatment of disorders of aging in companion animals; growthpromotant in livestock; and stimulation of wool growth in sheep.Further, the instant compounds are useful for increasing feedefficiency, promoting growth, increasing milk production and improvingthe carcass quality of livestock. Likewise, the instant compounds areuseful in a method of treatment of diseases or conditions which arebenefited by the anabolic effects of enhanced growth hormone levels thatcomprises the administration of an instant compound.

In particular, the instant compounds are useful in the prevention ortreatment of a condition selected from the group consisting of:osteoporosis; catabolic illness; immune deficiency, including that inindividuals with a depressed T_(4/T) ₈ cell ratio; bone fracture,including hip fracture; musculoskeletal impairment in the elderly;growth hormone deficiency in adults or in children; short stature inchildren; obesity; sleep disorders; cachexia and protein loss due tochronic illness such as AIDS or cancer; and treating patients recoveringfrom major surgery, wounds or bums, in a patient in need thereof.

In addition, the instant compounds may be useful in the treatment ofillnesses induced or facilitated by corticotropin releasing factor orstress- and anxiety-related disorders, including stress-induceddepression and headache, abdominal bowel syndrome, immune suppression,HIV infections, Alzheimer's disease, gastrointestinal disease, anorexianervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drugaddiction, and fertility problems.

It will be known to those skilled on the art that there are numerouscompounds now being used in an effort to treat the diseases ortherapeutic indications enumerated above. Combinations of thesetherapeutic agents some of which have also been mentioned above with thegrowth hormone secretagogues of this invention will bring additional,complementary, and often synergistic properties to enhance the growthpromotant, anabolic and desirable properties of these varioustherapeutic agents. In these combinations, the therapeutic agents andthe growth hormone secretagogues of this invention may be independentlypresent in dose ranges from one one-hundredth to one times the doselevels which are effective when these compounds and secretagogues areused singly.

Combined therapy to inhibit bone resorption, prevent osteoporosis andenhance the healing of bone fractures can be illustrated by combinationsof bisphosphonates and the growth hormone secretagogues of thisinvention. The use of bisphosphonates for these utilities has beenreviewed, for example, by Hamdy, N. A. T. Role of Bisphosphonates inMetabolic Bone Diseases. Trends in Endocrinol. Metab., , 4, 19-25(1993). Bisphosphonates with these utilities include alendronate,tiludronate, dimethyl-APD, risedronate, etidronate, YM-175, clodronate,pamidronate, and BM-210995. According to their potency, oral dailydosage levels of the bisphosphonate of between 0.1 mg and 5 g and dailydosage levels of the growth hormone secretagogues of this invention ofbetween 0.01 mg/kg to 20 mg/kg of body weight are administered topatients to obtain effective treatment of osteoporosis.

In the case of alendronate daily oral dosage levels of 0.1 mg to 50 mgare combined for effective osteoporosis therapy with 0.01 mg/kg to 20mg/kg of the growth hormone secretagogues of this invention.

Osteoporosis and other bone disorders may also be treated with compoundsof this invention in combination with calcitonin, estrogens, raloxifeneand calcium supplements such as calcium citrate or calcium carbonate.

Anabolic effects especially in the treatment of geriatric male patientsare obtained with compounds of this invention in combination withanabolic steroids such as oxymetholone, methyltesterone, fluoxymesteroneand stanozolol.

The compounds of this invention can be administered by oral, parenteral(e.g., intramuscular, intraperitoneal, intravenous or subcutaneousinjection, or implant), nasal, vaginal, rectal, sublingual, or topicalroutes of administration and can be formulated in dosage formsappropriate for each route of administration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound is admixed with at least one inert pharmaceutically acceptablecarrier such as sucrose, lactose, or starch. Such dosage forms can alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., lubricating agents such as magnesium stearate. In thecase of capsules, tablets and pills, the dosage forms may also comprisebuffering agents. Tablets and pills can additionally be prepared withenteric coatings.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water.Besides such inert diluents, compositions can also include adjuvants,such as wetting agents, emulsifying and suspending agents, andsweetening, flavoring, and perfuming agents.

Preparations according to this invention for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil and cornoil, gelatin, and injectable organic esters such as ethyl oleate. Suchdosage forms may also contain adjuvants such as preserving, wetting,emulsifying, and dispersing agents. They may be sterilized by, forexample, filtration through a bacteria-retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use.

Compositions for rectal or vaginal administration are preferablysuppositories which may contain, in addition to the active substance,excipients such as cocoa butter or a suppository wax.

Compositions for nasal or sublingual administration are also preparedwith standard excipients well known in the art.

The dosage of active ingredient in the compositions of this inventionmay be varied; however, it is necessary that the amount of the activeingredient be such that a suitable dosage form is obtained. The selecteddosage depends upon the desired therapeutic effect, on the route ofadministration, and on the duration of the treatment. Generally, dosagelevels of between 0.0001 to 10 mg/kg. of body weight daily areadministered to patients and animals, e.g., mammals, to obtain effectiverelease of growth hormone. Preferably, the dosage level will be about0.001 to about 25 mg/kg per day; more preferably about 0.01 to about 10mg/kg per day.

The following examples are provided for the purpose of furtherillustration only and are not intended to be limitations on thedisclosed invention.

EXAMPLE 1 ##STR59## Step A: N-Acetyl-Threo-(2R,3S)-β-methyltryptophanR-(+)-α-methylbenzyl Amine Salt

Racemic β-methyltryptophan was prepared by the method of Snyder andMatteson (J. Am. Chem. Soc. 1957, 79, 2217.) Isomer A (100 g) wassuspended in 1.25 L of 90/10 acetone water at 20° C. and 50 mL ofR-(+)-α-methylbenzylamine was added in one portion. The suspensioncleared briefly before a thick white suspension formed which quicklyturned to a solid mass. After aging overnight, an additional 500 mL ofacetone was added to facilitate agitation and filtration. The suspensionwas filtered and the cake washed with 500 mL of acetone and sucked to adamp cake. The solid was suspended in 2.5 L of 90/10 acetone/water andheated to boiling on a steam bath. The white slurry was allowed to coolto 20° C. overnight. The product was collected by filtration, washedwith acetone and dried yielding 39.1 g of the title compound. α=+9.1°(c=1, MeOH) Stereochemical assignments were made by comparison topublished compounds: J. Org. Chem. 1994, 59, 4239 and J. Org. Chem.1995, 60, 4978.

Step B: N-Acetyl-Threo-(2S,3R)-β-methyltryptophan S-(-)-α-methylbenzylAmine Salt

The mother liquors from the Step A were combined and concentrated to ca.1 L and 400 mL of 1N HCl was added. The resulting suspension was stirredfor 1 hr initially at 20° C. then at 0° C. The product was filtered andwashed with water until the filtrate was neutral. The product was suckedto a damp cake weighing 79 g. The solid was suspended in IL of 95%acetone/water and 40 mL of S-(-)-α-methylbenzylamine was added followedby 1 L of 90% acetone/water. After a few minutes a solid mass formed. Anadditional 500 mL of acetone was added and the mixture heated on a steambath for ca. 0.5 hr. This was then allowed to stand at 200C overnight.The product was collected by filtration, washed with 500 mL of acetone,and sucked to a damp cake. The product was suspended in 2 L of 95%acetone/water and heated on a steam bath to boiling. The whitesuspension was allowed to cool to 20° C. overnight. The product wascollected by filtration, washed with 500 mL of acetone and driedyielding 54 g. α=-9.0° (c=1, MeOH).

Step C: N-Acetyl-Erythro (2R,3R)-β-methyltryptophan R-(+)-α-methylbenzylamine salt

170 g of Isomer B (see ref. in Step A) which was a brittle foamcontaining ethyl acetate was dissolved in 2.5 L of ethyl acetatecontaining 100 mL of ethanol. To this was added 60 mL ofR-(+)-α-methylbenzylamine. After 10 min, an additional 2L of ethylacetate was added and the resulting thick suspension was aged at 20° C.for 3 days. The product was collected by filtration, washed with ethylacetate and and sucked to a damp cake. The salt was reslurried fourtimes with hot ethyl acetate containing 2% water (1×2.5 L, 2×6 L, and1×8 L). The yield of dried product was 43.2 g of salt. α=-19.6° (c=1,MeOH).

Step D: N-Acetyl-Erythro (2S,3S)-β-methyltryptophan S-(-)-α-methylbenzylAmine Salt

The mother liquors from the Step C were combined and concentrated to ca.2 L and washed twice with 500 mL 1N HCl. The washes were back extractedonce with ethyl acatate, and the combined ethyl acetate extracts washedtwice with brine. The solution was diluted to 6 L with ethyl acatate and60 mL of S-(-)-α-methylbenzylamine was added. After 10 min the resultingsuspension was heated to boiling. The suspension was allowed to cool toambient temperature with stirring overnight. The product was collectedby filtration washed with ethyl acetate and sucked to a damp cake. Thesalt was suspended in 6 L of ethyl acetate and suspension was heated toboiling. The suspension was allowed to cool to ambient temperature withstirring overnight. The product was collected by filtration washed withethyl acetate and dried. The yield of dried product was 65.8 g of salt.α=+19.7° (c=1, MeOH).

Step E: N-acetyl-threo-(2S 3R)-β-Methyltryptophan

The salt from Step B (53 g) was stirred with 400 mL 1N HCl at 20° C. for20 min. The suspension was filtered and the cake washed with water untilthe filtrate was neutral. The wet cake was used directly for the nextreaction. A sample was dried affording the title compound. α=-26.4°(c=1,MeOH).

Step F: threo-(2S,3R)-β-Methyltryptophan

The wet cake from Step E was suspended in with 400 mL of 1N HCl andrefluxed for 12 hours. The solution was cooled to 20° C., and half ofthe solution was used for Step G. The title compound isolated byadjusting the pH to 7.0 with sodium hydroxide, cooling the resultingsuspension to 0° C., filtering, washing the cake with water and drying.α=-29.3° (c=0.9, H₂ O).

Step G: N-t-BOC-threo-(2S,3R)-β-methyltryptophan

The pH of the aqueous solution from Step F was adjusted to 7 with sodiumhydroxide and cooled to 0° C. 20 g of potassium carbonate, 19 g ofdi-t-butyldicarbonate, and 150 mL of THF were added. The mixture wasallowed to warm slowly to ambient temperature overnight. The reactionwas extracted twice with ether, the aqueous acidified with 2N HCl andextracted twice with ethyl acetate. The combined ethyl acetate extractswere washed with brine, dried with MgSO₄, filtered and concentratedaffording 21.2 g of the title compound.

Step H: N-Acetyl-threo-(2R,3S)-β-methyltryptophan

The title compound was prepared following the procedure of Step E.α=+26.6° (c=1,MeOH).

Step I: Threo-(2R,3S)-β-Methyltryptophan

The title compound was prepared following the procedure of Step F.α=+30.6° (c=0.9, H₂ O).

Step J: N-t-BOC-threo-(2R,3S)-β-Methyltryptophan

The title compound was prepared following the procedure of Step G.

Step K: N-Acetyl-Erythro (2S,3S)-β-methyltryptophan

The salt from GRK example 4 (65 g) was stirred with 250 mL 1N HCl and1.5 L of ethyl acetate at ambient temperature for 5 min. The layers werepartitioned and the ethyl acetate layer was washed with 1N HCl, H₂ O andbrine, dried with MgSO₄, filtered and concentrated to afford the titlecompound as a brittle foam.

Step L: Erythro (2S,3S)-β-methyltryptophan

The product from Step K was suspended in with 500 mL of 2N HCl andrefluxed for 4 hours. The solution was cooled to 20° C., and half of thesolution was used for Step M. The title compound isolated as a foam byconcentrating the solution in vacuo.

Step M: N-t-BOC-Erythro (2S,3S)-β-methyltryptophan

The pH of the aqueous solution from Step F was adjusted to 7 with sodiumhydroxide and cooled to 0° C. 24 g of potassium carbonate, 22 g ofdi-t-butyldicarbonate, and 150 mL of THF were added. The mixture wasallowed to warm slowly to ambient temperature overnight. The reactionwas extracted twice with ether The aqueous acidified with 2N HCl.andextracted twice with ethyl acetate. The combined ethyl acetate extractswere washed with brine, dried with MgSO₄ filtered and concentrated. Thesolid was redissolved in ether, and the ether removed in vacuo whileflushing with hexanes. The resulting slurry was filtered and driedaffording 20.1 g of the title compound.

Step N: N-Acetyl-threo-(2R,3R)-β-methyltryptophan

The title compound was prepared following the procedure of Step K. α=°(c=1,MeOH).

Step O: Threo-(2R,3R)-β-methyltryptophan

The title compound was prepared following the procedure of Step L. α=°(c=0.9, H₂ O).

Step P: N-t-BOC-threo-(2R,3R)-β-methyltryptophan

The title compound was prepared following the procedure of Step M.

Step Q ##STR60##

To a solution of 51.0 g (0.177 mol) of 1'-(t-butyloxycarbonyl)spiro1H-indene-1,4'-piperidine! prepared by the method of Chambers, et al, J.Med. Chem., 1992, 35, 2036! in 200 ml of THF was added 430 ml (0.5M inTHF, 0.213 mol) of 9-BBN. The reaction mixture was heated at 70° C.until TLC analysis indicated that the starting material was consumed (18hrs). The solution was concentrated to ˜300 ml and then cooled to 0° C.and quenched with methanol (10 ml). 4N Sodium hydroxide (213 ml) and 30%hydrogen peroxide (108 ml) were added via an addition funnel over 45minutes. The reaction mixture was stirred for 3.5 hours and then solidsodium sulfite was added until starch paper indicated that no moreperoxides were present. The reaction mixture was extracted with ethylacetate (4×1 vol). The ethyl acetate layer was dried over magnesiumsulfate filtered and concentrated. The crude material was dissolved indichloromethane (300 ml) and the solution was cooled to 0° C. thencelite (25 g) and PCC (57 g) were added in five portions over 20minutes. The reaction mixture was warmed to room temperature and stirredovernight. The solution was then diluted with ether and filtered througha pad of a mixture of celite and florisil. Purification by flashchromotgraphy (silica gel, hexane/ethyl acetate, 5:1 to 3:1) gave 58.6 gof the title compound. ¹ H NMR (200 MHz, CDCl₃): 7.75-7.60 (m, 2H),7.50-7.44 (m, 2H), 4.30-4.15 (m, 2H), 2.85 (dt, 2H), 2.63 (s, 2H), 1.98(dt, 2H), 1.53-1.40 (m, 2H), 1.49 (s, 9H).

Step R ##STR61##

Potasium bis(trimethylsilyl)amide (127.5 ml, 0.5M) was added to theketone (16.0 g, 53 mmol) in THF (200 mL) at 0 ° C. The reaction mixturewas stirred for one hour and then N-phenyltrifluromethanesulfonamide wasadded. The ice bath was allowed to melt and the reaction mixture wasstirred overnight at room temperature. Water was added and the aqueouslayer was extracted with ethyl acetate (3×1 vol). The organic layer waswashed with brine and then dried over magnesium sulfate, filtered andthen concentrated. The crude product was purified by flashchromatography (hexane/ethyl acetate 8:1) to give the title compound(17.8 g ) as a waxy solid. ¹ HNMR (200 MHz, CDCl₃): 7.65-7.14 (m, 4H),6.66 (s, 1H), 4.30-4.15 (m, 2H), 3.24-2.96 (m, 2H), 2.06 (dt, 2H), 1.50(s, 9H), 1.49-1.38 (m, 2H).

Step S ##STR62##

A solution of 17.4 g of the intermediate from Step R, 11.0 ml oftriethylarnine, 634 mg of triphenylphosphine, and 240 mg of palladiumacetate in 72 ml of ethanol and 158.0 ml of DMF was purged for 10minutes with carbon monoxide and then stirred under a carbon monoxideatmosphere for 24 hours. The ethanol was removed in vacuum and thereaction mixture was diluted with water and extracted repeatedly withethyl acetate. The ethyl acetate layer was washed with 1N HCl, water,and brine and then dried over magnesium sulfate, filtered andconcentrated. Purification by flash chromatography (hexane/ethyl acetate8:1) provided 27.6 g of the title compound as a colorless oil. ¹ HNMR(200 MHz, CDCl₃): 8.0-7.94 (m,1H), 7.7 (s, 1H), 7.4-7.25 (m, 3H), 4.4(q,2H), 4.25-4.15 (m, 2H), 3.13 (dt, 2H), 2.03 (dt, 2H), 1.5 (s, 9H),1.55-1.35 (m, 2H), 1.4 (t, 3H).

Step T ##STR63##

To a suspension of Pd/C (1.7 g) in ethanol (300 ml) was added the titlecompound (27 g) from Step S. The reaction mixture was purged withhydrogen and then shaken under a hydrogen atmosphere for 3 hours. Themixture was purged with nitrogen and filtered through celite andconcentrated to give the title compound (27 g). The crude product wasdissolved in ethanol (200 ml ) and 2N sodium hydroxide (76 ml) wasadded. The reaction mixture was heated to 50° C. for three hours thencooled and the ethanol was removed under vacuum and the residue wasdissloved in ethyl acetate. IN HCl was added and the layers wereseparated and the aqueous layer was extracted with ethyl acetate (3×1vol). The combined organic layers were washed with saturated aqueousNaCl, dried over anhydrous sodium sulfate, filtered and concentrated toprovide the title compound (23.8 g) as a white solid. ¹ H NMR (200 MHz,CDCl₃): 7.50-7.42 (m, 1H), 7.34-7.12 (m, 3H), 4.22-4.04 (m, 3 H),3.06-2.84 (m, 2H), 2.40 (d, 2H), 1.88-1.6 (m, 4H), 1.50 (s, 9H).

Step U ##STR64##

The acid from Step T (23.5 g, 0.07 mol) was dissolved in toluene (150ml) and R-methylbenzylamine (9.02 ml) was added. The toluene solutionwas heated on a steam bath until everything was in solution. Thesolution was then seeded with crystals grown in the same way on a muchsmaller scale. The solution was allowed to sit overnight and then themixture was filtered to give 15.8 g of crystals. The crystals wererecrystalized from toluene two more times.The crystals (12 g) weredissolved in ethyl acetate/1N HCl and the organic layer was washed with1N HCl (2×1 vol) and brine. The organic layer was dried over magnesiumsulfate, filtered and concentrated to give 8.9 g of the title compound.α!^(D) =-16.9 (c=0.84, methanol)

Step V ##STR65##

The mother liqueurs from Step U were washed with 1N HCl (2×1 vol) andbrine dried over magnesium sulfate, filtered, and concentrated to giverecovered acid (15.4 g). To this acid in toluene (100 mL) was addedS-methylbenzylamine (5.95 mL). The crystals were recrystallized fourtimes from toluene as above to give 12.3 g of salt. The salt wasdissolved in ethyl acetate/1N HCl and washed with 1N HCl (2×1 vol) andbrine. The organic layer was dried over magnesium sulfate and filteredand concentrated to give the title compound (9.0 g). α!^(D) =+17.1(c=1.06, methanol).

Step W ##STR66##

A solution of the title compound from Step V (14.0 g, 42 mMol) indichloromethane was cooled to 0° C. and dimethylamine (25.4 mL, 2M inTHF) was added. The mixture was stirred for ten minutes at 0° C. andthen EDC and DMAP were added. The reaction mixture was stirred for fourhours at 0° C. and then quenched with 1N HCl. The aqueous layers wereextracted with dichloromethane and the combined organic layers were thenwashed with water and brine and dried over sodium sulfate. The crudeproduct was purified by flash chromatography (dichloromethane/acetone9:1) to give the title compound (12.2 g). HPLC analysis (chiralcel OD-R,50% 0.5N NaClO₄ /50% acetonitrile, 0.5 ml/min. E₁ retention time 20.8min (E₁ prepared from the intermediate in Example 1 Step U as in Example1 Step W; E₂ retention time 24.7 min) showed it to be approximately a1:200 mixture of enantiomers. ¹ HNMR (400 MHz, CDCl₃): 7.25-7.05(m, 4H),4.35 (t,1H), 4.20-4.10 (m, 2H), 3.25 (s, 3H), 3.05 (s, 3H), 2.90-2.85(m, 2H), 2.42-2.28 (m, 2H), 1.95 (dt, 1H), 1.75-1.60 (m, 2H), 1.52-1.50(m, 1H), 1.49 (s, 9H).

Step X ##STR67##

A sample of the title compound from Example 1 Step W was deprotectedwith a saturated solution of HCl in ethyl acetate as above to give thehydrochoride salt (6.3 g, 21 mmol). To this salt in dichloromethane at0° C. was added the intermediate prepared in Example | Step P (7.0 g, 22mmol), HOBT (4.4 g, 33 mmol), NMM (4.83 ml,44 mmol) and finally EDC(6.3g, 33 mmol). The reaction mixture was warmed to room temperature andstirred overnight. It was then poured into ethyl acetate and washed with1N HCl, saturated bicarb, and brine then dried over magnesium sulfate.The organic layer was filtered and concentrated. Purification by flashchromatography (ethyl acetate) provided the title compound (10 g, 17.9mmol).

Step Y ##STR68##

A solution of the N-Boc dipeptide from the previous step (1.32 g, 2.6mmol)) in ethyl acetate (8 mL) was cooled to 0° C. While stirring,HCl-EtOAc was added to the mixture (10 mL). The reaction was stirred for20 minutes, until TLC analysis indicated that the reaction was complete.The solution was then concentrated to remove the ethyl acetate to afford1.25 g of the product (100%). ESI-MS calc. for C28H33N4O2: 457; Found458 (M+H).

Step Z ##STR69##

To a solution of the intermediate from the previous step in methylenechloride was added N-Boc-3-methylaminobenzoic acid (62 mg), EDC(58 mg),HOBT (41 mg), and NMM (0.24 ml). The reaction mixture was stirredovernight and then loaded onto a prepTLC plate. Elution with methylenechloride/acetone (8:2) gave 79 mg.

Step AA ##STR70##

The intermediate from the previous step was stirred in ethyl acetate/HClfor two hours. Prep TLC purification gave 41 mg of the title compound.FAB-MS 592 (M+1).

EXAMPLE 2 ##STR71## Step A ##STR72##

To a solution of 1.0 g of 4-aminomethylbenzoic acid in 10 mL of 1N NaOH,10 mL of water and 20 mL of dioxane at 0° C. was 1.7 g ofditert-butylcarbonate and stirred overnight. The reaction mixture wasacidified to pH=2 and extracted with ethyl acetate. The combinedorganics were washed with brine, dried over anhydrous sodium sulfate andconcentrated to give the desired compound as a white solid.

Step B ##STR73##

To a solution of 1.20 g (5.8mmol) of 1'-methyl-1,2-dihydro-spiro3H-indole-3,4'-piperdine! (prepared as described in H. Ong et al J. Med.Chem. 1983, 23, 981-986) in 20 mL of dry dichloromethane at 0° C. wasadded triethylamine (0.90 mL; 6.4 mmol) and methanesulfonyl chloride(0.49 mL; 6.35 mmol) and stirred for 30 min. The reaction mixture waspoured into 15 mL of saturated aqueous sodium bicarbonate solution andextracted with dichloromethane (2×10 mL). The combined organics werewashed with brine (20 mL), dried over anhydrous potassium carbonate,filtered and the solvent removed under reduced pressure to yield 1.44 gof the methanesulfonamide derivative as pale yellow oil which was usedwithout purification.

To a solution of above crude product in 20 mL of dry 1,2-dichloroethaneat 0° C. was added 1.0 mL (9.30 mmol) of 1-chloroethyl chloroformate,and then stirred at RT for 30 min and finally at reflux for 1 h. Thereaction mixture was concentrated to approximately one third of thevolume and then diluted with 20 mL of dry methanol and refluxed for 1.5h. The reaction was cooled to RT and concentrated to approximately onehalf of the volume. The precipitate was filtered and washed with a smallvolume of cold methanol. This yielded 1.0 g of the piperidine HCl saltas a white solid. The filtrate was concentrated and a small volume ofmethanol was added followed by ether. The precipitated material was onceagain filtered, washed with cold methanol, and dried. This gave anadditional 0.49 g of the desired product. Total yield 1.49 g (70%). ¹ HNMR(CDCl₃, 200 MHz) d 7.43-7.20 (m, 3H), 7.10 (dd, 1H), 3.98 (bs, 2H),3.55-3.40 (bd, 2H), 3.35-3.10 (m, 2H), 2.99 (s, 3H), 2.15 (t, 2H), 2.00(t, 2H).

Step C ##STR74##

To a suspension of 1.2 g of the piperidine prepared in Step B in 15 mLof acetonitrile was added 0.50 mL of N-methylmorpholine, 1.00 g of (2R,3R)-N-tBOC-tryptophan, 0.80 g of HOBT, and 1.00 g of EDC and stirred atRT for 3h. The reaction mixture was diluted with 100 mL of ether andwashed with 50 mL of 0.05N HCl, 50 mL of saturated sodium bicarbonatesolution, dried over MgSO₄, and concentrated. A solution of the aboveintermediate in 50 mL of ethyl acetate at 0° C. was treated with HCl (g)for 2 min. and then stirred for 1 h. Dry ether (50 mL) was added, andthe precipitated solid was collected by filtration.

Step D ##STR75##

To a solution of 200 mg of the amino intermediate from Step C in 5 mL ofchloroform was added 100 mg of the acid intermediate from Step A, 65 mgof EDC and 110 mg of HOBT and stirred at room temperature for 16 h. Thereaction mixture was diluted with 20 mL of dichloromethane, washed with0.5N HCl (2×10 mL), saturated sodium bicarbonate solution, dried overanhydrous sodium sulfate and concentrated. This material was purified byflash chromatography with hexane-ethyl acetate (2:1) as the eluent togive the desired product. This material was dissolved in 3 mL of ethylacetate was treated with Hcl (gas) for 1 min. and stirred for 30minutes. Ether was added and the precipitate was collected byfiltration. FABMS Cacld. for C32H33N5O4S 585; Found 586.1 (m+1).

EXAMPLE 3 ##STR76##

The title compound was prepared from N-tBoc-2-naphthyl alanine and theprotected acid synthesized in Step A of Example 2 as described in theexperimental for Example 2. FABMS Cacld. for C34H36N4O4S 596; Found597.2 (m+1).

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inthe responsiveness of the mammal being treated for any of theindications with the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compounds selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims which follow and that such claims be interpreted as broadlyas is reasonable.

What is claimed is:
 1. A compound of the formula: ##STR77## wherein: R¹ is selected from the group consisting of:C₁ -C₁₀ alkyl, -aryl-, aryl (C₁ -C₆ alkyl)-, heteroaryl-, heteroaryl(C₁ -C₆ alkyl)-, (C₃ -C₇ cycloalkyl)-(C₁ -C₆ alkyl)-, (C₁ -C₅ alkyl)-K-(C₁ -C₅ alkyl)-, aryl-(C₀ -C₅ alkyl)-K-(C₁ -C₅ alkyl)-, heteroaryl-(C₀ -C₅ alkyl)-K-(C₁ -C₅ alkyl)-, and (C₃ -C₇ cycloalkyl)-(C₀ -C₅ alkyl)-K-(C₁ -C₅ alkyl)-,wherein K is --O--, --S(O)_(m) --, --N(R²)C(O)--, --C(O)N(R²)--,--OC(O--, --C(O)O--, --CR² ═CR² -- or --C.tbd.C--, wherein R² and the alkyl groups are optionally further substituted with 1 to 9 halo, --S(O)_(m) R^(2a), 1 to 3 of --OR^(2a), or --C(O)OR^(2a), and wherein aryl is phenyl or naphthyl, and heteroaryl is selected from indolyl, thiophenyl, benzofuranyl, benzothiopheneyl, aza-indolyl, pyridinyl, quinolinyl, and benzimidazolyl, wherein aryl and heteroaryl are unsubstituted or substituted with phenyl, phenoxy, halophenyl, 1 to 3 of --C₁ -C₆ alkyl, 1 to 3 of halo, 1 to 2 of --OR², methylenedioxy, --S(O)_(m) R², 1 to 2 of --CF₃, --OCF₃, nitro, --N(R²)(R²), --N(R²)C(O)(R²), --C(O)OR², --C(O)N(R²)(R²), --SO₂ N(R²)(R²), --N(R²)SO₂ -aryl, or --N(R²)SO₂ R² ; R^(1a) is hydrogen or C₁ -C₄ alkyl; R² is selected from the group consisting of:hydrogen, --C₁ -C₆ alkyl, --C₃ -C₇ cycloalkyl, and --CH₂ -phenyl, wherein the alkyl or the cyloalkyl is unsubstituted or substituted with hydroxyl, C₁ -C₃ alkoxy, thioalkyl, C(O)OR^(2a), and where, if two --C₁ -C₆ alkyl groups are present on one atom, the groups are optionally joined to form a C₃ -C₈ cyclic ring being selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, optionally substituted by hydroxyl; R^(2a) is hydrogen or C₁ -C₆ alkyl; B is selected from: ##STR78## R³ is selected from: hydrogen, --(CH₂)_(r) phenyl, --(CH₂)_(r) pyridyl, --(CH₂)_(r) thienyl, --(CH₂)_(r) benzimidazolyl, --(CH₂)_(r) quinolinyl, --(CH₂)_(r) naphthyl, --(CH₂)_(r) indolyl, --C₁ -C₁₀ alkyl, --C₃ -C₇ cycloalkyl, where the phenyl, pyridyl, naphthyl, indolyl, thienyl, benzimidazolyl, quinolinyl, and C₃ -C₇ cycloalkyl rings are optionally substituted by 1 to 3 substituents selected from the group consisting of:C₁ -C₆ alkyl, halogen, --OR², --NHSO₂ CF₃, --(CH₂)_(r) OR⁶, --(CH₂)_(r) N(R²)(R⁶), --(CH₂)_(r) (R⁶), --(CH₂)_(r) C(O)OR², --(CH₂)_(r) C(O)OR⁶, --(CH₂)_(r) OC(O)R², --(CH₂)_(r) OC(O)R⁶, --(CH₂)_(r) C(O)R², --(CH₂)_(r) C(O)R⁶, --(CH₂)_(r) C(O)N(R²)(R²), --(CH₂)_(r) C(O)N(R²)(R⁶), --(CH₂)_(r) N(R²)C(O)(R²), --(CH₂)_(r) N(R²)C(O)R⁶ --(CH²)_(r) N(R⁶)C(O)R², --(CH₂)_(r) N(R⁶)C(O)R⁶, --(CH₂)_(r) N(R²)C(O)OR², --(CH₂)_(r) N(R²)C(O)OR⁶, --(CH₂)_(r) N(R⁶)C(O)OR², --(CH₂)_(r) N(R⁶)C(O)OR⁶, --(CH₂)_(r) N(R²)C(O)N(R²)(R⁶), --(CH₂)_(r) N(R²)C(O)N(R²)(R²), --(CH₂)_(r) N(R⁶)C(O)N(R²)(R⁶), --(CH₂)_(r) N(R²)SO₂ R², --(CH₂)_(r) N(R⁶)SO₂ R², --(CH₂)_(r) N(R⁶)SO₂ R⁶, --(CH₂)_(r) OC(O)N(R²)(R⁶), --(CH₂)_(r) OC(O)N(R²)(R²), --(CH₂)_(r) SO₂ N(R²)(R⁶), --(CH₂)_(r) OC(O)N(R²)(R²), --(CH₂)_(r) SO₂ N(R²)(R⁶), --(CH₂)_(r) SO₂ N(R²)(R²), --(CH₂)_(r) N(R²)SO₂ N(R²)(R⁶), --(CH₂)_(r) N(R⁶)SO₂ N(R²)(R⁶), --(CH₂)_(r) S(O)_(m) R⁶, and --(CH₂)_(r) S(O)_(m) R² ; R^(3a) and R^(3b) are independently selected from: hydrogen, phenyl, phenoxy, halophenyl, --C₁ -C₆ alkyl, halogen, --OR², methylenedioxy,--S(O)_(m) R², --CF₃, --OCF₃, nitro, --N(R²)(R²), --N(R²)C(O)(R²), --C(O)OR², --C(O)N(R²)(R²), --SO₂ N(R²)(R²), --N(R²)SO₂ -aryl, and --N(R²)SO² R² ; E is selected from: --CH═CH--, ##STR79## which is optionally substituted with a substituent selected from: halo, hydroxy, --N(R²)(R²), C₁ -C₆ alkyl and C₁ -C₆ alkoxy; R⁴ and R⁵ are independently selected from hydrogen, C₁ -C₆ alkyl, and substituted C₁ -C₆ alkyl where the substituents are selected from halo, hydroxy, phenyl, and C₁ -C₆ alkoxycarbonyl; or R⁵ and R⁴ are taken together to form --(CH₂)_(d) --L_(a) (CH₂)_(e) --where L_(a) is --C(R²)₂ --, --O--, --S(O)_(m) -- or --N(R²)--, d and e are independently 1 to 3 and R² is as defined above; R^(4a) and R^(4b) are independently selected from: hydrogen, C₁ -C₆ alkyl, trifluoromethyl, phenyl, or substituted C₁ -C₆ alkyl where the substituents are selected from: imidazolyl, naphthyl, phenyl, indolyl, p-hydroxyphenyl, --OR², --S(O)_(m) R², --C(O)OR², C₃ -C₇ cycloalkyl, --N(R²)(R²), --C(O)N(R²)(R²); or R^(4a) and R_(4b) independently are joined to one or both of R⁴ or E (where E is other than --O--, --S--, or --CH═CH--) to form an alkylene bridge between the terminal nitrogen and the alkyl portion of the R^(4a) or R^(4b) and the R⁴ E group, wherein the bridge contain 1 to 8 carbons atoms; or R^(4a) and R^(4b) are joined to one another to form C₃ -C₇ cycloalkyl; R⁶ is selected from: hydrogen, C₁ -C₆ alkyl, and (CH₂)_(v) aryl, wherein the (CH₂)_(v) and alkyl groups are optionally substituted by --O(R²), --S(O)_(m) R², --C(O)OR², --C(O)N(R²)(R²), --SO₂ N(R²)(R²), or --N(R²)C(O)N(R²)(R²), wherein the aryl group is selected from: phenyl, pyridyl, 1H-tetrazolyl, triazolyl, oxadiazolyl, pyrazolyl, thiadiazoyl, and benzimidazol-2-yl, which is optionally substituted with C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, amino, or hydroxyl; X is selected from the group consisting of: hydrogen, --C--N, --(CH₂)_(q) N(R²)C(O)R², --(CH₂)_(q) N(R²)C(O)(CH₂)_(t) aryl, --(CH₂)_(q) N(R²)SO₂ (CH₂)_(t) aryl, --(CH₂)_(q) N(R²)SO₂ R², --(CH₂)_(q) N(R²)C(O)N(R²)(CH₂)_(t) aryl, --(CH₂)_(q) N(R²)C(O)N(R²)(R²), --(CH₂)_(q) C(O)N(R²)(R²), --(CH₂)_(q) C(O)N(R²)(CH₂)_(t) aryl, --(CH₂)_(q) C(O)OR², --(CH₂)_(q) C(O)O(CH₂)_(t) aryl, --(CH₂)_(q) OR², --(CH₂)_(q) OC(O)R², --(CH₂)_(q) OC(O)(CH²)_(t) aryl, --(CH₂)_(q) OC(O)N(R²)(R²), --(CH₂)_(q) C(O)R², --(CH₂)_(q) C(O)(CH₂)_(t) aryl, --(CH₂)_(q) N(R²)C(O)OR², --(CH₂)_(q) N(R²)SO₂ N(R²)(R²), --(CH₂)_(q) S(O)_(m) R², and --(CH₂)_(q) S(O)_(m) (CH₂)_(t) aryl, where R², (CH₂)_(q) and (CH₂)t group are optionally substituted with C₁ -C₄ alkyl, hydroxyl, C₁ -C₄ lower alkoxy, carboxyl, N(R²)(R²), CONH₂, S(O)_(m) CH₃, carboxylate C₁ -C₄ alkyl esters, or ₁ H-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or 1H-tetrazol-5-yl groups which are optionally substituted with halogen, --OR², --CON(R²)(R²), --C(O)OR², C₁ -C₄ alkyl, --S(O)_(m) R², or 1H-tetrazol-5-yl; Y is selected from the group consisting of:hydrogen, C₁ -C₁₀ alkyl, --(CH₂)_(t) aryl, --(CH₂)_(q) (C₃ -C₇ cycloalkyl), --(CH₂)_(q) --K--(C₁ -C₆ alkyl), --(CH₂)_(q) --K--(CH₂)_(t) aryl, --(CH₂)_(q) --K--(CH₂)_(t) (C₃ -C₇ cycloalkyl containing O, NR² S) and --(CH₂)_(q) --K--(CH₂)_(t) (C₃ -C₇ cycloalkyl), where K is --O--, --S(O)_(m) --, --C(O)NR² --, --CH═CH--, --C.tbd.C--, --N(R²)C(O)--, --C(O)NR² --, --C(O)O--, or --OC(O)--, and where the alkyl, R², (CH₂)_(q) and (CH₂)_(t) groups are optionally substituted by C₁ -C₄ alkyl, hydroxyl, C₁ -C₄ lower alkoxy, carboxyl, --CONH₂ or a carboxylate C₁ -C₄ alkyl ester, and aryl is phenyl, naphthyl, pyridyl, 1-H-tetrazol-5-yl, thiazolyl, imidazoly, indolyl, oxadiazoyl, pyrimidinyl, thiadiazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrazinyl, or isothiazolyl which is optionally substituted with halogen, --OR², --C(O)OR², N(R²)(R²), --C(O)N(R²)(R²), nitro, cyano, benzyl, C₁ -C₄ alkyl, --S(O)_(m) R², or 1H-tetrazol-5-yl; D is selected from: --N(R⁷)--, --S(O)_(m) --, --C(O)-- and --C(H)(R⁷)--, wherein R⁷ is selected from: --R², --OR², --(CH₂)_(q) aryl, --C(O)R², --C(O)(CH₂)_(q) aryl, --SO₂ R², --SO₂ (CH₂)_(q) aryl, --C(O)N(R²)(R²), --C(O)N(R²)(CH₂)_(q) aryl, --C(O)OR², 1-H-tetrazol-5-yl, --SO₂ N(R²)aryl, --SO₂ N(R²)(R²) and the (CH₂)_(q) is optionally substituted by C₁ -C₄ alkyl, and the R² and aryl are optionally further substituted with a substituent selected from: --OR^(2a), --O(CH₂)_(q) aryl, --C(O)OR^(2a), --C(O)(CH₂)_(q) aryl, --C(O)N(R^(2a))(R^(2a)), C(O)N(R^(2a))(CH₂)_(l) aryl, halogen, --N(R^(2a))(R^(2a)), --C₁ -C₄ alkyl, 1,2,4-triazolyl, 1-H-tetrazol-5-yl, -C(O)NHSO₂ R^(2a), --S(O)_(m) R^(2a), --C(O)NHSO₂ (CH₂)_(q) aryl, --N(R²)C(O)N(R^(2a))(R^(2a)), --N(R^(2a))C(O)N(R^(2a))(CH₂)_(q) aryl, --N(R^(2a))(R^(2a)), --N(R^(2a))C(O)R^(2a)), --N(R^(2a))C(O)(CH₂)_(q) aryl, --OC(O)N(R^(2a))(R^(2a)), --OC(O)N(R^(2a))(CH₂)_(q) aryl; l is 0, 1 or 2; m is 0, 1, or 2; n is 2; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, or 3; t is 0, 1, 2, or 3; v is 0, 1, or 2; x is 0, 1, 2, or 3; y is 0, 1, 2, or 3, with the proviso that if E is --CH═CH--, y is other than 0;and pharmaceutically acceptable salts and individual diastereomers thereof.
 2. The compound of claim 1 of the formula: ##STR80## wherein: R¹ is selected from the group consisting of:C₁ -C₁₀ alkyl, -aryl-, aryl (C₁ -C₆ alkyl)-, heteroaryl-, heteroaryl(C₁ -C₆ alkyl)-, (C₃ -C₇ cycloalkyl)-(C₁ -C₆ alkyl)-, (C₁ -C₅ alkyl)-K-(C₁ -C₅ alkyl)-, aryl-(C₀ -C₅ alkyl)-K-(C₁ -C₅ alkyl)-, heteroaryl-(C₀ -C₅ alkyl)-K-(C₁ -C₅ alkyl)-, and (C₃ -C₇ cycloalkyl)-(C₀ -C₅ alkyl)-K-(C₁ -C₅ alkyl)-,wherein K is --O--, --S(O)_(m) --, --N(R²)C(O)--, --C(O)N(R²)--,--OC(O)--, --C(O)O--, --CR² ═CR² -- or --C.tbd.C--, wherein R² and the alkyl groups are optionally further substituted with 1 to 9 halo, --S(O)_(m) R^(2a), 1 to 3 of --OR^(2a), or --C(O)OR^(2a), and wherein aryl is phenyl or naphthyl, and heteroaryl is selected from indolyl, thiophenyl, benzofuranyl, benzothiopheneyl, aza-indolyl, pyrindinyl, quinolinyl, and benzimidazolyl, wherein aryl and heteroaryl are unsubstituted or substituted with phenyl, phenoxy, halophenyl, 1 to 3 of --C₁ -C₆ alkyl, 1 to 3 of halo, 1 to 2 of --OR², methylenedioxy, --S(O)_(m) R², 1 to 2 of --CF₃, --OCF₃, nitro, --N(R²)(R²), --N(R²)C(O)(R²), --C(O)OR², --C(O)N(R²)(R²), --SO₂ N(R²)(R²), --N(R²)SO₂ -aryl, or --N(R²)SO₂ R² ; R² is selected from the group consisting of:hydrogen, --C₁ -C₆ alkyl, --C₃ -C₇ cycloalkyl, and --CH₂ -phenyl,wherein the alkyl or the cyloalkyl is unsubstituted or substituted with hydroxyl, C₁ -C₃ alkoxy, thioalkyl, --C(O)OR^(2a), and wherein, if two --C₁ -C₆ alkyl groups are present on one atom, the groups are optionally joined to form a C₃ -C₈ cyclic ring being selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine; B is selected from: ##STR81## R³ is selected from: hydrogen, phenyl, pyridyl, naphthyl, indolyl, benzimidazolyl, thienyl, quinolinyl, where the phenyl, pyridyl, naphthyl, benzimidazolyl, thienyl, quinolinyl, and indolyl are optionally substituted by 1 to 3 substituents selected from the group consisting of:C₁ -C₆ alkyl, halogen, --OR², --(CH₂)_(r) OR⁶, --(CH₂)_(r) N(R²)(R⁶), --(CH₂)_(r) (R⁶), --(CH₂)_(r) C(O)OR², --(CH₂)_(r) C(O)OR⁶, --(CH₂)_(r) C(O)R², --(CH₂)_(r) C(O)R⁶, --(CH₂)_(r) C(O)N(R²)(R²), --(CH₂)_(r) C(O)N(R²)(R⁶), --(CH₂)_(r) N(R²)C(O)(R²), --(CH₂)_(r) N(R²)C(O)R⁶ --(CH₂)_(r) N(R⁶)C(O)R², --(CH₂)_(r) N(R⁶)C(O)R⁶, --(CH₂)_(r) N(R²)C(O)OR², --(CH₂)_(r) N(R²)C(O)OR⁶, --(CH₂)_(r) N(R⁶)C(O)OR², --(CH₂)_(r) N(R⁶)C(O)OR⁶, --(CH₂)_(r) N(R²)C(O)N(R²)(R⁶), --(CH₂)_(r) N(R²)C(O)N(R²)(R²), --(CH₂)_(r) N(R⁶)C(O)N(R²)(R⁶), --(CH₂)_(r) N(R²)SO₂ R², --(CH₂)_(r) N(R⁶)SO₂ R², --(CH₂)_(r) N(R⁶)SO₂ R⁶, --(CH₂)_(r) OC(O)N(R²)(R⁶), --(CH₂)_(r) SO₂ N(R²)(R⁶), --(CH₂)_(r) SO₂ N(R²)(R⁶), --(CH₂)_(r) SO₂ N(R²)(R²), --(CH₂)_(r) S(O)_(m) R⁶, and --(CH₂)_(r) S(O)_(m) R² ; R^(3a) and R^(3b) are independently selected from: hydrogen, phenyl, phenoxy, halophenyl, --C₁ -C₆ alkyl, halogen, --OR², methylenedioxy, --S(O)_(m) R², --CF₃, --OCF₃, nitro, --N(R²)(R²), --N(R²)C(O)(R²), --C(O)OR², --C(O)N(R²)(R²), --SO₂ N(R²)(R²), --N(R²)SO₂ -aryl, and --N(R²)SO² R² ; E is selected from: --CH═CH--, ##STR82## which is optionally substituted with a substituent selected from: halo, hydroxy, --N(R²)(R²), C₁ -C₆ alkyl and C₁ -C₆ alkoxy; R⁴ and R⁵ are independently selected from hydrogen, C₁ -C₆ alkyl, and substituted C₁ -C₆ alkyl where the substituents are selected from halo, hydroxy, phenyl, and C₁ -C₆ alkoxycarbonyl; or R⁵ and R⁴ are taken together to form --(CH₂)_(d) --L_(a) (CH₂)_(e) --where L_(a) is --C(R²)₂ --, --O--, --S(O)_(m) -- or --N(R²)--, d and e are independently 1 to 3 and R² is as defined above; R^(4a) and R^(4b) are independently selected from: hydrogen, C₁ C₆ alkyl, trifluoromethyl, phenyl, or substituted C₁ -C₆ alkyl where the substituents are selected from: imidazolyl, naphthyl, phenyl, indolyl, p-hydroxyphenyl, --OR², --S(O)_(m) R², --C(O)OR², C₃ -C₇ cycloalkyl, --N(R²)(R²), --C(O)N(R²)(R²); or R^(4a) and R^(4b) independently are joined to one or both of R⁴ or E (were E is other than --O--, --S--, or --CH═CH--) to form an alkylene bridge between the terminal nitrogen and the alkyl portion of the R^(4a) or R^(4b) and the R⁴ E group, wherein the bridge contain 1 to 5 carbons atoms; or R^(4a) and R^(4b) are joined to one another to form C₃ -C₇ cycloalkyl; R⁶ is selected from: hydrogen, C₁ -C₆ alkyl, and (CH₂)_(v) aryl, wherein the (CH₂)_(v) and alkyl groups are optionally substituted by --O(R²), --S(O)_(m) R², --C(O)OR², --C(O)N(R²)(R²), --SO₂ N(R²)(R²), or --N(R²)C(O)N(R²)(R²), wherein the aryl group is selected from: phenyl, pyridyl, 1H-tetrazolyl, triazolyl, oxadiazolyl, pyrazolyl, thiadiazoyl, and benzimidazol-2-yl, which is optionally substituted with C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, amino, or hydroxyl; X is selected from the group consisting of: hydrogen, --C.tbd.N, --(CH₂)_(q) N(R²)C(O)R², --(CH₂)_(q) N(R²)C(O)(CH₂)_(t) aryl, --(CH₂)_(q) N(R²)SO₂ (CH₂)_(t) aryl, --(CH₂)_(q) N(R²)SO₂ R², --(CH₂)_(q) N(R²)C(O)N(R²)(CH₂)_(t) aryl, --(CH₂)_(q) N(R²)C(O)N(R²)(R²), --(CH₂)_(q) C(O)N(R²)(R²), --(CH₂)_(q) C(O)N(R²)(CH₂)_(t) aryl, --(CH₂)_(q) C(O)OR², --(CH₂)_(q) C(O)O(CH₂)_(t) aryl, --(CH₂)_(q) OR², --(CH₂)_(q) OC(O)R², --(CH₂)_(q) OC(O)(CH²)_(t) aryl, --(CH₂)_(q) OC(O)N(R²)(R²), --(CH₂)_(q) C(O)R², --(CH₂)_(q) C(O)(CH₂)_(t) aryl, --(CH₂)_(q) N(R²)C(O)OR², --(CH₂)_(q) N(R²)SO₂ N(R²)(R²), --(CH₂)_(q) S(O)_(m) R², and --(CH₂)_(q) S(O)_(m) (CH₂)_(t) aryl, where R², (CH₂)_(q) and (CH₂)t group is optionally substituted with C₁ -C₄ alkyl, hydroxyl, C₁ -C₄ lower alkoxy, carboxyl, N(R²)(R²), CONH₂, S(O)_(m) CH₃, carboxylate C₁ -C₄ alkyl esters, or 1H-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or 1H-tetrazol-5-yl groups which are optionally substituted with halogen, --OR², --CON(R²)(R²), --C(O)OR², C₁ -C₄ alkyl, --S(O)_(m) R², or 1H-tetrazol-5-yl; Y is selected from the group consisting of:hydrogen, C₁ -C₁₀ alkyl, --(CH₂)_(t) aryl, --(CH₂)_(q) (C₃ -C₇ cycloalkyl), --(CH₂)_(q) --K--(C₁ -C₆ alkyl), --(CH₂)_(q) --K--(CH₂)_(t) aryl, --(CH₂)_(q) --K--(CH₂)_(t) (C₃ -C₇ cycloalkyl containing O, NR² S) and --(CH₂)_(q) --K--(CH₂)_(t) (C₃ -C₇ cycloalkyl), where K is O, S(O)_(m), C(O)NR², CH═CH, C.tbd.C, N(R²)C(O), C(O)NR², C(O)O, or OC(O), andwhere the alkyl, R², (CH₂)_(q) and (CH₂)_(t) groups are optionally substituted by C₁ -C₄ alkyl, hydroxyl, C₁ -C₄ lower alkoxy, carboxyl, --CONH₂ or a carboxylate C₁ -C₄ alkyl ester, and aryl is phenyl, naphthyl, pyridyl, 1-H-tetrazol-5-yl, thiazolyl, imidazoly, indolyl, oxadiazoyl, pyrimidinyl, thiadiazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrazinyl, or isothiazolyl which is optionally substituted with halogen, --OR², --C(O)OR², N(R²)(R²), --C(O)N(R²)(R²), nitro, cyano, benzyl, C₁ -C₄ alkyl, --S(O)_(m) R², or 1H-tetrazol-5-yl; D is selected from: --N(R⁷)--, --S(O)_(m) --, --C(O)-- and --C(H)(R⁷)--, wherein R⁷ is selected from: --R², --(CH₂)_(q) aryl, --C(O)R², --SO₂ R², --C(O)N(R²)(R²), --C(O)OR², 1-H-tetrazol-5-yl, --SO₂ N(R²)aryl, --SO₂ N(R²)(R²) and the (CH₂)_(q) are optionally substituted by C₁ -C₄ alkyl, and the R² and aryl are optionally further substituted with a substituent selected from: --OR^(2a), --C(O)OR² a, --C(O)N(R^(2a))(R^(2a)), halogen, --C₁ -C₄ alkyl, and the aryl is selected from of triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, and 1H-tetrazolyl; l is 0, 1 or 2; m is 0, 1, or 2; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, or 3; t is 0, 1, 2, or 3; v is 0, 1, or 2; x is 0, 1, 2, or 3; y is 0, 1, 2, or 3, with the proviso that if E is --CH═CH--, y is other than 0;and pharmaceutically acceptable salts and individual diastereomers thereof.
 3. The compound of claim 1 of the formula: ##STR83## wherein: R¹ is selected from the group consisting of: ##STR84## or their regioisomers where not specified; R² is selected from the group consisting of:hydrogen, --C₁ -C₆ alkyl, --C₃ -C₇ cycloalkyl, and -CH₂ -phenyl,wherein the alkyl or the cyloalkyl is unsubstituted or substituted with hydroxyl, C₁ -C₃ alkoxy, thioalkyl, --C(O)OR^(2a), and wherein, if two --C₁ -C₆ alkyl groups are present on one atom, the groups are optionally joined to form a C₃ -C₈ cyclic ring being selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine; R^(2a) is hydrogen, or C_(1-C) ₄ alkyl; B is selected from: ##STR85## R³ is selected from: hydrogen or phenyl, wherein the phenyl is substituted in the ortho position by a substituent selected from the group consisting of: C₁ -C₆ alkyl, halogen, --OR², --(CH₂)_(r) OR⁶, --(CH₂)_(r) N(R²)(R⁶), --(CH₂)_(r) (R⁶), --(CH₂)_(r) C(O)OR², --(CH₂)_(r) C(O)OR⁶, --(CH₂)_(r) C(O)R², --(CH₂)_(r) C(O)R⁶, --(CH₂)_(r) C(O)N(R²)(R²), --(CH₂)_(r) C(O)N(R²)(R⁶), --(CH₂)_(r) SO₂ N(R²)(R⁶), --(CH₂)_(r) SO₂ N(R²)(R²), --(CH₂)_(r) S(O)_(m) R⁶, and --(CH₂)_(r) S(O)_(m) R² ; R^(3a) and R^(3b) are independently selected from: hydrogen, --C₁ -C₆ alkyl and halogen; E is selected from: --CH═CH--, ##STR86## which is optionally substituted with a substituent selected from: halo, hydroxy, --N(R²)(R²), C₁ -C₆ alkyl and C₁ -C₆ alkoxy; R⁴ and R⁵ are independently selected from hydrogen, C₁ -C₆ alkyl, and substituted C₁ -C₆ alkyl where the substituents are selected from halo, hydroxy, phenyl, and C₁ -C₆ alkoxycarbonyl; or R⁵ and R⁴ are taken together to form --(CH₂)_(d) --L_(a) (CH₂)_(e) --where L_(a) is --C(R²)₂ --, --O--, --S(O)_(m) -- or --N(R²)--, d and e are independently 1 to 3 and R² is as defined above; R^(4a) and R^(4b) are independently selected from: hydrogen, C₁ -C₆ alkyl, or substituted C₁ -C₆ alkyl where the substituents are selected from: imidazolyl, naphthyl, phenyl, indolyl, and p-hydroxyphenyl; R⁶ is selected from: hydrogen, C₁ -C₆ alkyl, and (CH₂)_(v) aryl, wherein the (CH₂)_(v) and alkyl groups are optionally substituted by --O(R²), --S(O)_(m) R², --C(O)OR², --C(O)N(R²)(R²), --SO₂ N(R²)(R²), or --N(R²)C(O)N(R²)(R²), wherein the aryl group is selected from: phenyl, pyridyl, 1H-tetrazolyl, triazolyl, oxadiazolyl, pyrazolyl, thiadiazoyl, and benzimidazol-2-yl, which is optionally substituted with C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, amino, or hydroxyl; X is selected from the group consisting of: hydrogen, ##STR87## and further selected from the following group of heterocycles ##STR88## wherein the heterocycle is optionally substituted with a substituent selected from: --N(R²)(R²), --O(R²), C₁ -C₃ alkyl, halogen, and trifluoromethyl; Y is selected from the group consisting of: hydrogen, ##STR89## or their regioisomers whereof where not specified; D is selected from: --N(R⁷)--, --S(O)_(m) --, --C(O)-- and --C(H)(R⁷)--, wherein R⁷ is selected from: --R², --(CH₂)_(q) aryl, --C(O)R², --SO₂ R², --C(O)N(R²)(R²), --C(O)OR², 1-H-tetrazol-5-yl, --SO₂ N(R²)aryl, --SO₂ N(R²)(R²) and the (CH₂)_(q) is optionally substituted by C₁ -C₄ alkyl, and the R² and aryl are optionally further substituted with a substituent selected from: --OR^(2a), --C(O)OR^(2a), --C(O)N(R^(2a))(R^(2a)), halogen, --C₁ -C₄ alkyl, and the aryl is selected from of triazolyl, oxadiazolyl, 1H-tetrazolyl, and thiadiazolyl; l is 0, 1 or 2; m is 0, 1, or 2; q is 0, 1, 2, 3, or 4; r is 0, 1, 2, or 3; t is 0, 1, 2, or 3; v is 0, 1, or 2; y is 1 or 2;and pharmaceutically acceptable salts and individual diastereomers thereof.
 4. The compound of claim 1 of the formula: ##STR90## wherein B is selected from the group consisting of: ##STR91## E' is selected from: --CH═CH--CH₂ --NH₂, --CH═CH--CH(CH₃)--NH₂,--CH═CH--C(CH₃)₂ --NH₂, or phenyl substituted with --CH₂ --NH₂, --CH(CH₃)--NH₂, or --C(CH₃)₂ --NH₂ ;and pharmaceutically acceptable salts and individual diastereomers thereof.
 5. The compound of claim 4 of the formula: ##STR92## wherein B is selected from the group consisting of: ##STR93## and pharmaceutically acceptable salts and individual diastereomers thereof.
 6. A compound which is selected from the group consisting of: ##STR94## and pharmaceutically acceptable salts and individual diastereomers thereof where not otherwise specified.
 7. A pharmaceutical composition which comprises an inert carrier and the compound of claim
 1. 8. A pharmaceutical composition useful for increasing the endogenous production or release of growth hormone in a human or an animal which comprises an inert carrier and an effective amount of the compound of claim 1 in combination with an additional growth hormone secretagogue.
 9. A method for increasing levels of endogenous growth hormone in a human or an animal which comprises administering to said human or animal an effective amount of the compound of claim
 1. 10. A method for increasing levels of endogenous growth hormone in a human or an animal which comprises administering to such human or animal an effective amount of the compound of claim 1 in combination with an additional growth hormone secretagogue. 